Aryl group-or aromatic heterocyclic group-substituted aminoquinolone derivatives and anti-hiv agent

ABSTRACT

Disclosed are an aryl group- or heterocyclic group-substituted aminoquinolone compound represented by the formula (Ia), (Ib) or (Ic): ##STR1## wherein each of the substitutents are defined in the specification, or a salt of the compound, and an AIDS curing agent containing the same as an effective ingredient.

This is a continuation division of application Ser. No. 08/341,295 filedNov. 15, 1994, now U.S. Pat. No. 5,519,016 which is a continuation ofapplication Ser. No. 08/066,985 filed May 25, 1993 now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to derivatives of aminoquinolone, and usestherefor.

AIDS (Acquired Immuno-deficiency Syndrome) is now generally accepted asbeing caused by the Human Immunodeficiency Virus (HIV).

The aetiology of AIDS is not yet precisely known, but it is known thatHIV mainly infects CD₄ lymphocytes, generally of the class ofhelper/inducer cells. Lymphocyte numbers gradually decrease, and thiseventually leads to severe cellular immunodeficiency.

Very considerable research has been put into finding a cure for AIDS,but the development of a vaccine has proven extremely difficult.Accordingly, other avenues have also been pursued. One such avenue isthe development of antiviral agents.

An antiviral agent currently on the market for the treatment of AIDS isAZT (Azidothymidine). The method of action of AZT is to inhibit theinherent reverse transcriptase of HIV, thus retarding or stoppingreproduction of the virus. However, such a treatment can, at the best,only prolong life expectancy, and cannot cure AIDS completely. Otherantiviral agents which have been developed act in a similar fashion.

Such inhibitory agents are also associated with side effects, such asdisorders of the bone marrow and digestive system, and it has also beenfound that tolerance, or even total resistance, can be induced in thevirus with a high frequency. Such resistant viruses can be generatedeven in patients receiving long-term therapy.

In order to overcome the above problems, it would be highly desirable todevelop new antiviral agents which could be used either alone, or incombination therapy with known agents.

Anti-HIV activity has recently been reported for the compound DR-3355,which is an optical isomer (S-isomer) of Ofloxacin, a syntheticanti-bacterial agent. Ofloxacin has a quinolone skeleton J. Nozaki,Renard et al., AIDS (1990), 4, p. 1283!. Attempts by the presentinventors to reproduce the antiviral activity of DR-3355, using themethod of R. Pauwel, et al., (infra), have failed.

WO-A-90-13542 discloses the anti-HIV activity of Norfloxacin, Enoxacin,Ciprofloxacin, Lomefloxacin, Difloxacin and Tosufloxacin but, again,these compounds demonstrate little or no anti-HIV activity when testedby the Pauwel method. These compounds also possess a quinolone skeleton.

SUMMARY OF THE INVENTION

We have now discovered a series of new quinolone derivatives which,whilst exhibiting considerably weaker antibacterial activity than thosequinolone derivatives described above, exhibit very considerablyenhanced anti-HIV activity. The new compounds disclosed herein haveincreased lipophilicity, and possess a diamine substituent which is,itself, further substituted by an aromatic group, such as an aryl groupor an aromatic heterocyclic group. The compounds of the invention areboth capable of inhibiting HIV replication and inhibiting the cytopathiceffect (CPE) of HIV, and so are useful as agents to inhibit HIVreplication and as anti-AIDS agents.

In a first aspect, the present invention provides a compound of thegeneral formula (Ia), (Ib) or (Ic): ##STR2## in which X represents ahydrogen atom or a halogen atom;

Y represents a hydrogen atom, a halogen atom, a lower alkyl group, anamino group, or an amino group substituted by one or two groups selectedfrom lower alkyl and aralkyl groups;

Z represents a carboxyl group or a 5-tetrazolyl group;

Q represents a nitrogen atom or a group of formula (d): ##STR3## whereR² represents a hydrogen atom, a halogen atom, a lower alkoxy group, alower alkoxy group substituted by one or more halogen atoms, a loweralkyl group, a lower alkyl group substituted by one or more halogenatoms;

W represents an oxygen atom or a sulfur atom;

T represents a C₁₋₄ alkylene group or a C₂₋₄ alkenylene group, saidgroups optionally being substituted by a lower alkyl group;

R¹ represents: a hydrogen atom; a lower alkenyl group which mayoptionally be substituted by one or more halogen atoms; a lower alkynylgroup; an amino group which may optionally be substituted by one or morelower alkyl groups; a cycloalkyl group which may optionally besubstituted by at least one halogen atom; a lower alkoxy group; an arylgroup which may optionally be substituted by at least one substituent R⁰as defined below; a 5- or 6-membered aromatic heteromonocyclic grouphaving one or two heteroatoms selected from N, O and S, said ringoptionally being substituted by at least one substituent R⁰ as definedbelow; a fused aromatic group consisting of a benzene ring fused with a5- or 6-membered aromatic heteromonocyclic group as defined above, saidfused group optionally being substituted by at least one substituent R⁰as defined below; a lower alkyl group; or a lower alkyl groupsubstituted by at least one substituent selected from

halogen atoms, hydroxyl groups, carboxyl groups, alkanoyloxy groups,cycloalkyl groups, aryl groups which may optionally be substituted by atleast one substituent R⁰ as defined below, 5- or 6-membered aromaticheteromonocyclic groups having one or two heteroatoms selected from N, Oand S, said ring optionally being substituted by at least onesubstituent R⁰ as defined below, fused aromatic groups as defined above,said fused group optionally being substituted by at least onesubstituent R⁰ as defined below, or an amino group represented by theformula (e): ##STR4## wherein R⁹ and R¹⁰ separately represent a hydrogenatom or a lower alkyl group, or R⁹ and R¹⁰, together with the nitrogenatom to which they are attached, form a 3- to 7-membered saturatedmonocyclic group comprising at least one further heteroatom selectedfrom N, O and S, or when Q is a group of formula (d), then R¹ and R² maytogether represent a group of formula (f): ##STR5## wherein A representsa hydrogen atom, or a lower alkyl group which may optionally besubstituted by at least one substituent selected from halogen atoms,hydroxy and lower alkoxy groups; G represents a nitrogen atom or a groupof formula (g): ##STR6## G¹ represents a methylene group, a carbonylgroup, an oxygen atom, a sulfur atom or a group of formula --N(R¹¹)--,where R¹¹ represents a hydrogen atom or a lower alkyl group; and p=0 or1;

R represents a group of formula (h) or (i): ##STR7## where R³ and R⁶each represents an aryl group which may optionally be substituted by atleast one substituent R⁰ as defined below; a 5- or 6-membered aromaticheteromonocyclic group having one or two heteroatoms selected from N, Oand S, said ring optionally being substituted by at least onesubstituent R⁰ as defined below; a fused aromatic group consisting of abenzene ring fused with a 5- or 6-membered aromatic heteromonocyclicgroup as defined above, said fused group optionally being substituted byat least one substituent R⁰ as defined below;

R⁴, R⁵ and R⁷ may be the same or different, and each represents ahydrogen atom or a lower alkyl group;

R⁸ represents a hydrogen atom, a lower alkyl group, a hydroxy group or alower alkoxy group;

n=1 or 2;

m=0 or 1;

n'=1 or 2; and

n"=1, 2, 3 or 4; and

substituent R⁰ are selected from halogen atoms, nitro groups, hydroxygroups, lower alkyl groups which may optionally be substituted with atleast one halogen atom, lower alkoxy groups, and amino groups which mayoptionally be substituted with one or two lower alkyl groups, and whenthere are two or more substituents R⁰, each may be the same ordifferent,

or a pharmaceutically acceptable salt or ester thereof and an AIDScuring agent containing the compound represented by the above formula(Ia), (Ib) or (Ic) or an ester thereof as an active ingredient.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following, the present invention is explained in detail.

The compounds represented by the formula (Ia), (Ib) and (Ic) includecompounds represented by the formulae (Ia-1), (Ib-1) and (Ic-1) and theformulae (Ia-2), (Ib-2) and (Ic-2) shown below. ##STR8## wherein X, Y,Z, W, Q, T, R¹, R³ to R⁸, m, n, n' and n" each have the same meanings asdefined above.

Further, as the compounds represented by the formula (Ia), (Ib) and(Ic), there may be preferably mentioned compounds represented by theformulae (Ia-3), (Ib-3) and (Ic-3), the formulae (Ia-4), (Ib-4) and(Ic-4), the formulae (Ia-5), (Ib-5) and (Ic-5), and the formulae (Ia-6)and (Ia-7). ##STR9## wherein A, X, Y, Z, W, R, T and R¹ each have thesame meanings as defined above; --OR¹² represents a lower alkoxy groupwhich may be substituted by a halogen atom(s), particularly adifluoromethoxy group; R¹³ represents a hydrogen atom, a halogen atom ora lower alkyl group which may be substituted by a halogen atom(s); andA' represents a hydrogen atom or a lower alkyl group which may besubstituted by a halogen atom(s).

In the present invention, the compounds represented by the formulae(Ia-3), (Ib-3), (Ic-3) and (Ia-6) are preferred, and the compoundsrepresented by the formula (Ia-3) and the formula (Ia-6) wherein A' is alower alkyl group substituted by a fluorine atom(s) are particularlypreferred.

When X represents a halogen atom in the above formulae (Ia), (Ib) and(Ic), suitable examples include fluorine, chlorine, bromine and iodine,and X is preferably hydrogen, fluorine or chlorine, particularlypreferably fluorine or chlorine, and most preferably fluorine.

Suitable examples of Y in the above formulae (Ia), (Ib) and (Ic) includea hydrogen atom; a halogen atom such as fluorine, chlorine, bromine andiodine; a straight or branched chain C₁ to C₄ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl and isobutyl; an amino group; amono-C₁ to C₄ alkylamino group such as methylamino, ethylamino,propylamino, isopropylamino and butylamino; a di-C₁ to C₄ alkylaminogroup such as dimethylamino, diethylamino, dipropylamino,diisopropylamino and dibutylamino; a mono aralkylamino group such asbenzylamino and phenylethylamino; and a diaralkylamino group such asdibenzylamino.

The above Y is preferably hydrogen, fluorine, amino, methyl or ethyl,particularly preferably hydrogen, fluorine, amino or methyl, mostpreferably hydrogen.

Suitable examples of Z in the above formulae (Ia) and (Ic) include acarboxyl group which may be protected or a 5-tetrazolyl group. Where thecompound of the present invention is an ester, for example, where Zrepresents a carboxyl group, then suitable ester groupings include a C₁to C₄ alkyl, aralkyl, C₁ to C₄ alkanoyloxyalkyl, C₁ to C₄alkoxycarbonyloxyalkyl, N,N-dialkyl-substituted aminocarbonylalkyl,N,N-dialkyl-substituted aminoalkyl, alkyl substituted by a 5- or6-membered saturated monocyclic group having one or two hetero atomsselected from N, O and S, and (5-methyl- or5-phenyl-2-oxo-1,3-dioxolen-4-yl)-methyl. The above Z is preferably acarboxyl group which may be protected.

W in the above formula (Ib) is an oxygen atom or a sulfur atom,particularly preferably a sulfur atom.

Suitable examples of T in the above formula (Ic) include a C₁ to C₄alkylene group which may be substituted by a C₁ to C₄ alkyl, such asmethylene, ethylidene (--CH(CH₃)--), ethylene, trimethylene, propyleneand tetramethylene, or a C₂ to C₄ alkenylene group which may besubstituted by a C₁ to C₄ alkyl, such as --CH═CH-- and --C(CH₃)═CH--. Tis preferably ethylidene, --CH═CH-- or --C(CH₃)═CH--, particularlypreferably ethylidene.

Suitable examples of the halogen atom represented by R² of the formula(d) represented by Q in the above formulae (Ia), (Ib) and (Ic) includefluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

Suitable examples of the lower alkyl group which may be substituted by ahalogen atom(s) represented by R² include a C₁ to C₄ alkyl group such asmethyl, ethyl, propyl, isopropyl and butyl, or a fluorine-substituted C₁to C₄ lower alkyl group such as fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl and 4-fluorobutyl, andmethyl or trifluoromethyl is preferred.

Suitable examples of the lower alkoxy group which may be substituted bya fluorine atom(s) represented by R² include a C₁ to C₄ alkoxy groupsuch as methoxy, ethoxy, propoxy, isopropoxy and butoxy, or afluorine-substituted C₁ to C₄ alkoxy group such as fluoromethoxy,difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2- or 3-fluoropropoxyand 4-fluorobutoxy, preferably methoxy, ethoxy, mono-, di- ortrifluoromethoxy or 2-fluoroethoxy, particularly preferably methoxy andmono-, di- or trifluoromethoxy, most preferably methoxy ordifluoromethoxy.

The above R² is preferably hydrogen; a halogen atom such as fluorine andchlorine; a lower alkyl group which may be substituted by a halogen atomsuch as methyl and trifluoromethyl; a lower alkoxy group which may besubstituted by a halogen atom such as methoxy, ethoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy or 2-fluoroethoxy; particularlypreferably a methoxy group which may be substituted by a fluorineatom(s). Further, in the formula (Ia), a compound wherein R² is amethoxy group or a difluoromethoxy group is most preferred.

In the present specification, a lower alkyl/alkoxy group includes nomore than 6 carbon atoms, preferably no more than 4, particularly 1, 2or 3.

In the present invention, the characteristic feature of the compoundsrepresented by the formulae (Ia), (Ib) and (Ic) resides in that R in theformulae is a group represented by the formula (h) or (i) and to thenitrogen atom is bound the above aryl group or the aromatic heterocyclicgroup of R³ or R⁶, each of which may be substituted by R⁰.

In the above formula (h), n is preferably 1. In the formula (i), the sumof n' and n" is preferably 3, 4 or 5 and particularly preferably 3 or 4.m is preferably 0.

In the above formulae (h) and (i), the aryl group represented by R³ orR⁶ may include phenyl and naphthyl, and the aromatic heteromonocyclic orfused heterocyclic group (hereinafter referred to as an "aromaticheterocyclic group") may include 2-thienyl, 2-furyl, 2-oxazolyl,2-thiazolyl, 2-imidazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl,2-pyrazinyl, 3-pyridazinyl, 2-benzoxazolyl, 2-benzothiazolyl and2-benzimidazolyl.

As the substituent R⁰ substituted on the above aryl or aromaticheterocyclic group, there may be mentioned a halogen atom such asfluorine, chlorine, bromine and iodine; a nitro group; a hydroxyl group;a straight or branched chain C₁ to C₄ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, s-butyl, isobutyl and t-butyl; afluorine-substituted C₁ to C₄ alkyl group such as mono-, di- ortrifluoromethyl, 2-fluoroethyl, 2- or 3-fluoropropyl and 2-, 3- or4-fluorobutyl; a C₁ to C₄ alkoxy group such as methoxy, ethoxy, propoxy,isopropoxy and butoxy; an amino group, a mono-C₁ to C₄ alkyl-substitutedamino group such as methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, s-butylamino andt-butylamino; and a di-C₁ to C₄ alkyl-substituted amino group such asdimethylamino, diethylamino, dipropylamino, diisopropylamino,dibutylamino, diisobutylamino and ethyl(methyl)amino.

As the above R³ and R⁶, the aromatic heterocyclic group which may besubstituted by R⁰ as mentioned above is preferred, and those wherein Ris represented by the formula (h) and R³ in the formula (h) is anaromatic heterocyclic group which may be substituted by R⁰ areparticularly preferred. Among them, those in which R³ is a 5- or6-membered heteromonocyclic group having 1 or 2 nitrogen atom, which maybe substituted by R⁰, are particularly preferred. Further preferred arethose in which R³ is a pyridyl group, pyrazinyl group or pyrimidinylgroup which may be substituted by R⁰ and R³ is particularly preferably2-pyrimidinyl group.

Also, a compound wherein R is represented by the formula (h) and R³ inthe formula (h) is a phenyl group substituted by R⁰ as mentioned aboveis preferred.

As the above R³, there may be preferably mentioned phenyl; 2-pyridyl;2-pyrazinyl; 2- or 4-pyrimidinyl; dimethoxy-2-pyrimidinyl; 2-thiazolyl;2-benzoxazolyl; 2-benzothiazolyl; a phenyl substituted by fluorine,chlorine, methoxy, nitro, trifluoromethyl, amino or dimethylamino at 2-,3- or 4-position; a methoxy-, amino- or nitro-substituted 2-pyridyl; anda chlorine-, methyl- or ethyl-substituted 2- or 4-pyrimidinyl;particularly preferred are phenyl; 2-pyridyl; 2-pyrazinyl; 2- or4-pyrimidinyl; 2-thiazolyl; a phenyl substituted by fluorine, chlorine,methoxy, nitro, trifluoromethyl, amino or dimethylamino at 2-, 3- or4-position; a methoxy- or nitro-substituted 2-pyridyl; or a chlorine-,methyl- or ethyl-substituted 2- or 4-pyrimidinyl.

R is most preferably a 4-(2-pyrimidinyl)piperazin-1-yl.

In the above formulae (h) and (i), the lower alkyl group represented byR⁴, R⁵ or R⁷ may include a C₁ to C₄ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl and t-butyl, preferably a methyl oran ethyl.

In the above formula (i), the lower alkyl group represented by R⁸ mayinclude a straight or branched chain C₁ to C₄ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl,preferably methyl, ethyl, propyl or isopropyl, more preferably methyl orethyl.

In the above formula (i), the lower alkoxy group represented by R⁸ mayinclude a C₁ to C₄ alkoxy group such as methoxy, ethoxy, propoxy,isopropoxy and butoxy, preferably methoxy, ethoxy or propoxy.

The above R⁴, R⁵, and R⁷ are preferably a hydrogen atom, methyl, ethyl,propyl or isopropyl, particularly preferably a hydrogen atom, methyl orethyl.

The above R⁸ is preferably a hydrogen atom, a hydroxy group, methyl,ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy, particularlypreferably a hydrogen atom, a hydroxy group, methyl, ethyl, methoxy orethoxy.

In the above formulae (Ia) and (Ib), the lower alkyl group and loweralkoxy group represented by R¹ may include the same straight or branchedchain C₁ to C₄ alkyl group mentioned as the lower alkyl grouprepresented by the above R⁸ and the same C₁ to C₄ alkoxy group mentionedas the lower alkoxy group represented by the above R⁸.

As the lower alkyl group having a substituent(s) represented by theabove R¹, there may be mentioned a hydroxy C₁ to C₄ alkyl group such as2-hydroxyethyl, 2- or 3-hydroxypropyl, 2-, 3- or 4-hydroxybutyl; acarboxyl C₁ to C₄ alkyl group such as carboxymethyl, 1- or2-carboxyethyl, 1- or 3-carboxypropyl, 1-carboxybutyl and1-carboxy-2-hydroxyethyl; a halogeno C₁ to C₄ alkyl group such asfluoro-, chloro-, bromo- or iodomethyl, 2-(fluoro-, chloro-, bromo- oriodo)ethyl, 2- or 3-(fluoro-, chloro-, bromo- or iodo)propyl, 2-, 3- or4-(fluoro-, chloro-, bromo- or iodo)butyl, difluoromethyl,trifluoromethyl and 2,2,2-trifluoroethyl; a C₃ to C₆ cycloalkyl C₁ to C₄alkyl group such as cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopropylpropyland cyclopropylbutyl; a C₁ to C₄ alkanoyloxy C₁ to C₄ alkyl group suchas 2-acetoxyethyl, 2- or 3-acetoxypropyl, 2-, 3- or 4-acetoxybutyl,2-propionyloxyethyl and 2-butyryloxyethyl; a C₁ to C₄ alkyl groupsubstituted by the same aryl group or aromatic heterocyclic group asmentioned as examples of R³ and R⁶ in the above formulae (h) and (i), orthe C₁ to C₄ alkyl group substituted by a substituent represented by theabove formula (e).

The lower alkyl group represented by R⁹ or R¹⁰ in the above formula (e)may include the same straight or branched chain C₁ to C₄ alkyl group asmentioned as the lower alkyl group represented by the above R⁸, and thesaturated heteromonocyclic group formed by R⁹ and R¹⁰ in combination inthe above formula (e) may include each group of aziridino, azetidino,pyrrolidino, piperidino, morpholino, thiomorpholino and piperazino.

Suitable examples of the mono- or di-lower alkyl-substituted amino grouprepresented by the above R¹ include a mono-C₁ to C₄ alkylamino groupsuch as methylamino, ethylamino, propylamino, isopropylamino andbutylamino, and a di-C₁ to C₄ alkylamino group such as dimethylamino,diethylamino, dipropylamino, diisopropylamino and dibutylamino.

Suitable examples of the cycloalkyl group which may be substituted by ahalogen represented by the above R¹ include a C₃ to C₆ cycloalkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and ahalogeno-C₃ to C₆ cycloalkyl group such as 2-fluoro-, 2-chloro- or2-bromocyclopropyl, 2,2-difluorocyclopropyl,2-chloro-2-fluorocyclopropoyl, 2-fluorocyclobutyl, 2-fluorocyclopentyland 2-fluorocyclohexyl.

Suitable examples of the lower alkenyl group which may be substituted bya halogen represented by the above R¹ include a C₂ to C₅ lower alkenylgroup such as vinyl, 1- or 2-propenyl, 1-, 2- or 3-butenyl and3,3-dimethyl-2-propenyl; and a halogeno-C₂ to C₄ lower alkenyl groupsuch as 3,3-dichloro-2-propenyl, 2,3-dichloro-2-propenyl and4-chloro-3-butenyl.

Suitable examples of the lower alkynyl group represented by the above R¹include a C₂ to C₄ lower alkynyl group such as ethynyl, 1- or 2-propynyland 2-butynyl.

Suitable examples of R¹ as mentioned above preferably include hydrogenatom; methyl, ethyl, propyl, isopropyl, butyl or t-butyl as the loweralkyl group; 2-hydroxyethyl, 2- or 3-hydroxypropyl, carboxymethyl, 1- or2-carboxyethyl, fluoromethyl, 2-fluoroethyl, 2-chloroethyl,3-fluoropropyl, 3-chloropropyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, cyclopropylmethyl, 2-acetoxyethyl, 2- or3-acetoxypropyl, phenylmethyl, 1- or 2-phenylethyl, naphthylmethyl, 2-,3- or 4-fluorophenylmethyl, 2,4-, 3,4- or 2,6-difluorophenylmethyl, 2-,3- or 4-methylphenylmethyl, 2-, 3- or 4-chlorophenylmethyl, 2-, 3- or4-methoxyphenylmethyl, 2-thienylmethyl, 2-furylmethyl, 2-pyridylmethyl,2-pyrimidinylmethyl, 2-aminoethyl, 2-methylaminoethyl,2-dimethylaminoethyl, 2-morpholinoethyl or 2-piperidinoethyl as thelower alkyl group having a substituent(s); an amino group; methylamino,ethylamino or dimethylamino as the amino group substituted by a loweralkyl; methoxy, ethoxy or propoxy as the lower alkoxy group;cyclopropyl, cyclobutyl, cyclopentyl or 2-fluorocyclopropyl as thecycloalkyl group which may be substituted by a halogen; phenyl,naphthyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2,4-, 3,4-or 2,6-difluorophenyl or 2-, 3- or 4-methylphenyl as the aryl group;2-thiazolyl, 2-oxazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl,2-benzoxazolyl or 2-benzothiazolyl as the aromatic hetero cyclic group;vinyl, 2-propenyl, 3,3-dimethylpropenyl or 3,3-dichloropropenyl as thelower alkenyl group which may be substituted by a halogen; and ethynylor 2-propynyl as the lower alkynyl group.

As to the above R¹, it is particularly preferred that the lower alkylgroup is methyl, ethyl, propyl or isopropyl; the lower alkyl grouphaving a substituent(s) is 2-hydroxyethyl, carboxymethyl, 2-fluoroethyl,2-acetoxyethyl, phenylmethyl, phenylethyl, 2-pyridylmethyl,2-dimethylaminoethyl or 2-morpholinoethyl; an amino group; the aminogroup substituted by a lower alkyl is methylamino; the lower alkoxygroup is methoxy; the cycloalkyl group which may be substituted by ahalogen is cyclopropyl or 2-fluorocyclopropyl; the aryl group which maybe substituted by a halogen(s) is phenyl, 2-, 3- or 4-fluorophenyl or2,4-difluorophenyl; the lower alkenyl group which may be substituted bya halogen is vinyl or 2-propenyl; and the lower alkynyl group is2-propynyl.

When the bond represented by the formula (f) is formed by R¹ in theabove formulae (Ia) and (Ib), and R² in combination, A in the formula(f) may include a hydrogen atom; a C₁ to C₄ alkyl group such as methyl,ethyl, propyl, isopropyl and butyl; a halogeno-C₁ to C₄ alkyl group suchas fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2- or 3-fluoropropyl and 2-,3- or 4-fluorobutyl; a hydroxy-C₁ to C₄ alkyl group such ashydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 4-hydroxybutyl; and aC₁ to C₄ alkoxy-C₁ to C₄ alkyl group such as methoxymethyl,ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, methoxypropyland methoxybutyl. In the formula (f), G may include a nitrogen atom or atrivalent group represented by the formula (g), G¹ may include amethylene group, a carbonyl group, an oxygen atom, a sulfur atom and--N(R¹¹)-- where R¹¹ represents a hydrogen atom, a C₁ to C₄ alkyl groupsuch as methyl, ethyl, propyl and butyl; and p is 0 or 1.

In the above formula (f), A is preferably a hydrogen atom, a lower alkylgroup which may be substituted by a halogen, such as methyl, ethyl,propyl, isopropyl and fluoromethyl, particularly preferably methyl andfluoromethyl. As G, a group represented by the formula (g) is preferred.Also, as G¹, it is preferably an oxygen atom or a sulfur atom,particularly suitably an oxygen atom. p is most preferably 1.

When the above formula (Ia), (Ib) or (Ic) has a carboxyl group in themolecule (i.e. as Z or R¹), such a carboxyl group may be protected. Assuch a protective group, there may be mentioned a group which is easilydeprotected in vivo to be converted into a carboxyl group, including aC₁ to C₄ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl andisobutyl; an aralkyl group such as benzyl and phenylethyl; a C₁ to C₄alkanoyloxyalkyl group such as acetoxymethyl and pivaloyloxymethyl; a C₁to C₄ alkoxycarbonyloxyalkyl group such as 1-(ethoxycarbonyloxy)ethyland 1-(isopropoxycarbonyloxy)ethyl; an N,N-dialkyl-substitutedaminocarbonylalkyl group such as N,N-dimethylaminocarbonylmethyl; andN,N-dialkyl-substituted aminoalkyl group such as2-(N,N-dimethylamino)ethyl; an alkyl group substituted by a 5- or6-membered saturated heteromonocyclic group having one or two heteroatoms selected from N, O and S such as 2-morpholinoethyl,2-piperidinoethyl and 2-(4-methylpiperidino)ethyl; or a (5-methyl-(or5-phenyl)-2-oxo-1,3-dioxolen-4-yl)methyl group.

In the compounds represented by the above formulae (Ia) and (Ib), whenR¹ is a hydrogen atom, tautomers shown by the following formulae canexist, and all of these tautomers are included in the present invention.##STR10##

In the present invention, the compound represented by the above formula(Ia), (Ib) or (Ic) can be made into a pharmaceutically acceptable salt,if necessary.

Such a salt may include an acid addition salt of a mineral acid such asa hydrochloride, a hydrobromide, a hydroiodide, a sulfate and aphosphate; an acid addition salt of an organic acid such as amethanesulfonate, an ethanesulfonate, a benzenesulfonate, ap-toluenesulfonate, an oxalate, a maleate, a fumarate, a tartarate and acitrate; or a metal salt of a carboxylic acid such as a sodium salt, apotassium salt, a calcium salt, a magnesium salt, a manganese salt, aniron salt and an aluminum salt.

The compounds of the above formula (Ia), (Ib) or (Ic) of the presentinvention can exist as a hydrate.

Compounds represented by the above formula (Ia), (Ib) or (Ic) areexemplified in Tables 1 to 20 below.

                  TABLE 1                                                         ______________________________________                                         ##STR11##                                                                    R.sup.3         R.sup.3                                                       ______________________________________                                        Phenyl          2-Oxazolyl                                                    2-Fluorophenyl  2-Thiazolyl                                                   3-Fluorophenyl  2-Imidazolyl                                                  4-Fluorophenyl  2-Pyridyl                                                     2-Chlorophenyl  6-Methoxy-2-pyridyl                                           3-Chlorophenyl  3-Nitro-2-pyridyl                                             4-Chlorophenyl  3-Amino-2-pyridyl                                             2-Methoxyphenyl 3-Methylamino-2-pyridyl                                       3-Methoxyphenyl 3-Ethylamino-2-pyridyl                                        4-Methoxyphenyl 3-Fluoro-2-pyridyl                                            2-Nitrophenyl   3-Pyridyl                                                     3-Nitrophenyl   4-Pyridyl                                                     4-Nitrophenyl   2-Benzoxazolyl                                                2-Aminophenyl   5-Chloro-2-benzoxazolyl                                       3-Aminophenyl   2-Benzothiazolyl                                              4-Aminophenyl   5-Methyl-2-benzothiazolyl                                     2-Dimethylaminophenyl                                                                         2-Benzimidazolyl                                              3-Dimethylaminophenyl                                                                         2-Pyrimidinyl                                                 4-Dimethylaminophenyl                                                                         5-Chloro-2-pyrimidinyl                                        2-Trifluoromethylphenyl                                                                       4-Methoxy-2-pyrimidinyl                                       3-Trifluoromethylphenyl                                                                       4,6-Dimethoxy-2-pyrimidinyl                                   4-Trifluoromethylphenyl                                                                       4-Pyrimidinyl                                                 2,4-Difluorophenyl                                                                            5-Chloro-6-methyl-4-pyrimidinyl                                               3-Pyridazinyl                                                                 6-Chloro-3-pyridazinyl                                                        2-Pyrazinyl                                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR12##                                                                    R.sup.3         R.sup.3                                                       ______________________________________                                        Phenyl          2-Oxazolyl                                                    2-Fluorophenyl  2-Thiazolyl                                                   3-Fluorophenyl  2-Imidazolyl                                                  4-Fluorophenyl  2-Pyridyl                                                     2-Chlorophenyl  6-Methoxy-2-pyridyl                                           3-Chlorophenyl  3-Nitro-2-pyridyl                                             4-Chlorophenyl  3-Amino-2-pyridyl                                             2-Methoxyphenyl 3-Methylamino-2-pyridyl                                       3-Methoxyphenyl 3-Ethylamino-2-pyridyl                                        4-Methoxyphenyl 3-Fluoro-2-pyridyl                                            2-Nitrophenyl   3-Pyridyl                                                     3-Nitrophenyl   4-Pyridyl                                                     4-Nitrophenyl   2-Benzoxazolyl                                                2-Aminophenyl   5-Chloro-2-benzoxazolyl                                       3-Aminophenyl   2-Benzothiazolyl                                              4-Aminophenyl   5-Methyl-2-benzothiazolyl                                     2-Dimethylaminophenyl                                                                         2-Benzimidazolyl                                              3-Dimethylaminophenyl                                                                         2-Pyrimidinyl                                                 4-Dimethylaminophenyl                                                                         5-Chloro-2-pyrimidinyl                                        2-Trifluoromethylphenyl                                                                       4-Methoxy-2-pyrimidinyl                                       3-Trifluoromethylphenyl                                                                       4,6-Dimethoxy-2-pyrimidinyl                                   4-Trifluoromethylphenyl                                                                       4-Pyrimidinyl                                                 2,4-Difluorophenyl                                                                            5-Chloro-6-methyl-4-pyrimidinyl                                               3-Pyridazinyl                                                                 6-Chloro-3-pyridazinyl                                                        2-Pyrazinyl                                                   ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR13##                                                                    R.sup.3         R.sup.3                                                       ______________________________________                                        Phenyl          2-Oxazolyl                                                    2-Fluorophenyl  2-Thiazolyl                                                   3-Fluorophenyl  2-Imidazolyl                                                  4-Fluorophenyl  2-Pyridyl                                                     2-Chlorophenyl  6-Methoxy-2-pyridyl                                           3-Chlorophenyl  3-Nitro-2-pyridyl                                             4-Chlorophenyl  3-Amino-2-pyridyl                                             2-Methoxyphenyl 3-Methylamino-2-pyridyl                                       3-Methoxyphenyl 3-Ethylamino-2-pyridyl                                        4-Methoxyphenyl 3-Fluoro-2-pyridyl                                            2-Nitrophenyl   3-Pyridyl                                                     3-Nitrophenyl   4-Pyridyl                                                     4-Nitrophenyl   2-Benzoxazolyl                                                2-Aminophenyl   5-Chloro-2-benzoxazolyl                                       3-Aminophenyl   2-Benzothiazolyl                                              4-Aminophenyl   5-Methyl-2-benzothiazolyl                                     2-Dimethylaminophenyl                                                                         2-Benzimidazolyl                                              3-Dimethylaminophenyl                                                                         2-Pyrimidinyl                                                 4-Dimethylaminophenyl                                                                         5-Chloro-2-pyrimidinyl                                        2-Trifluoromethylphenyl                                                                       4-Methoxy-2-pyrimidinyl                                       3-Trifluoromethylphenyl                                                                       4,6-Dimethoxy-2-pyrimidinyl                                   4-Trifluoromethylphenyl                                                                       4-Pyrimidinyl                                                 2,4-Difluorophenyl                                                                            5-Chloro-6-methyl-4-pyrimidinyl                                               3-Pyridazinyl                                                                 6-Chloro-3-pyridazinyl                                                        2-Pyrazinyl                                                   ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                         ##STR14##                                                                    R.sup.3         R.sup.3                                                       ______________________________________                                        Phenyl          2-Thiazolyl                                                   2-Fluorophenyl  2-Imidazolyl                                                  3-Fluorophenyl  2-Pyridyl                                                     4-Fluorophenyl  6-Methoxy-2-pyridyl                                           2-Chlorophenyl  3-Nitro-2-pyridyl                                             3-Chlorophenyl  6-Nitro-2-pyridyl                                             4-Chlorophenyl  3-Amino-2-pyridyl                                             2-Methoxyphenyl 3-Methylamino-2-pyridyl                                       3-Methoxyphenyl 3-Ethylamino-2-pyridyl                                        4-Methoxyphenyl 3-Fluoro-2-pyridyl                                            2-Ethoxyphenyl  3-Pyridyl                                                     2-Nitrophenyl   4-Pyridyl                                                     3-Nitrophenyl   2-Benzoxazolyl                                                4-Nitrophenyl   5-Chloro-2-benzoxazolyl                                       2-Aminophenyl   2-Benzothiazolyl                                              3-Aminophenyl   5-Methyl-2-benzothiazolyl                                     4-Aminophenyl   2-Benzimidazolyl                                              2-Dimethylaminophenyl                                                                         2-Pyrimidinyl                                                 3-Dimethylaminophenyl                                                                         5-Chloro-2-pyrimidinyl                                        4-Dimethylaminophenyl                                                                         4-Methoxy-2-pyrimidinyl                                       2-Trifluoromethylphenyl                                                                       4,6-Dimethoxy-2-pyrimidinyl                                   3-Trifluoromethylphenyl                                                                       4-Pyrimidinyl                                                 4-Trifluoromethylphenyl                                                                       6-Ethyl-4-pyrimidinyl                                         2,4-Difluorophenyl                                                                            6-Chloro-4-pyrimidinyl                                        2-Methylphenyl  5-Chloro-6-methyl-4-pyrimidinyl                               3-Methylphenyl  3-Pyridazinyl                                                 3-Hydroxyphenyl 6-Chloro-3-pyridazinyl                                        2-Oxazolyl      2-Pyrazinyl                                                   ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                         ##STR15##                                                                    R.sup.3         R.sup.3                                                       ______________________________________                                        Phenyl          2-Oxazolyl                                                    2-Fluorophenyl  2-Thiazolyl                                                   3-Fluorophenyl  2-Imidazolyl                                                  4-Fluorophenyl  2-Pyridyl                                                     2-Chlorophenyl  6-Methoxy-2-pyridyl                                           3-Chlorophenyl  3-Nitro-2-pyridyl                                             4-Chlorophenyl  3-Amino-2-pyridyl                                             2-Methoxyphenyl 3-Methylamino-2-pyridyl                                       3-Methoxyphenyl 3-Ethylamino-2-pyridyl                                        4-Methoxyphenyl 3-Fluoro-2-pyridyl                                            2-Nitrophenyl   3-Pyridyl                                                     3-Nitrophenyl   4-Pyridyl                                                     4-Nitrophenyl   2-Benzoxazolyl                                                2-Aminophenyl   5-Chloro-2-benzoxazolyl                                       3-Aminophenyl   2-Benzothiazolyl                                              4-Aminophenyl   5-Methyl-2-benzothiazolyl                                     2-Dimethylaminophenyl                                                                         2-Benzimidazolyl                                              3-Dimethylaminophenyl                                                                         2-Pyrimidinyl                                                 4-Dimethylaminophenyl                                                                         5-Chloro-2-pyrimidinyl                                        2-Trifluoromethylphenyl                                                                       4-Methoxy-2-pyrimidinyl                                       3-Trifluoromethylphenyl                                                                       4,6-Dimethoxy-2-pyrimidinyl                                   4-Trifluoromethylphenyl                                                                       4-Pyrimidinyl                                                 2,4-Difluorophenyl                                                                            5-Chloro-6-methyl-4-pyrimidinyl                                               3-Pyridazinyl                                                                 6-Chloro-3-pyridazinyl                                                        2-Pyrazinyl                                                   ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                         ##STR16##                                                                    R.sup.3         R.sup.3                                                       ______________________________________                                        Phenyl          2-Oxazolyl                                                    2-Fluorophenyl  2-Thiazolyl                                                   3-Fluorophenyl  2-Imidazolyl                                                  4-Fluorophenyl  2-Pyridyl                                                     2-Chlorophenyl  6-Methoxy-2-pyridyl                                           3-Chlorophenyl  3-Nitro-2-pyridyl                                             4-Chlorophenyl  3-Amino-2-pyridyl                                             2-Methoxyphenyl 3-Methylamino-2-pyridyl                                       3-Methoxyphenyl 3-Ethylamino-2-pyridyl                                        4-Methoxyphenyl 3-Fluoro-2-pyridyl                                            2-Nitrophenyl   3-Pyridyl                                                     3-Nitrophenyl   4-Pyridyl                                                     4-Nitrophenyl   2-Benzoxazolyl                                                2-Aminophenyl   5-Chloro-2-benzoxazolyl                                       3-Aminophenyl   2-Benzothiazolyl                                              4-Aminophenyl   5-Methyl-2-benzothiazolyl                                     2-Dimethylaminophenyl                                                                         2-Benzimidazolyl                                              3-Dimethylaminophenyl                                                                         2-Pyrimidinyl                                                 4-Dimethylaminophenyl                                                                         5-Chloro-2-pyrimidinyl                                        2-Trifluoromethylphenyl                                                                       4-Methoxy-2-pyrimidinyl                                       3-Trifluoromethylphenyl                                                                       4,6-Dimethoxy-2-pyrimidinyl                                   4-Trifluoromethylphenyl                                                                       4-Pyrimidinyl                                                 2,4-Difluorophenyl                                                                            5-Chloro-6-methyl-4-pyrimidinyl                               4-Methylphenyl  3-Pyridazinyl                                                 4-Hydroxyphenyl 6-Chloro-3-pyridazinyl                                                        2-Pyrazinyl                                                   ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                         ##STR17##                                                                    R.sup.1     R.sup.2      R.sup.3                                              ______________________________________                                        Methyl      Methoxy      3-Chlorphenyl                                        4-Fluorophenyl                                                                            Methoxy      4-Nitrophenyl                                        2,4-Difluorophenyl                                                                        Methoxy      4-Dimethylaminophenyl                                Methyl      Difluoromethoxy                                                                            2-Methlyphenyl                                       Methyl      Difluoromethoxy                                                                            2-Methoxyphenyl                                      Methyl      Difluoromethoxy                                                                            3-Methoxyphenyl                                      Methyl      Difluoromethoxy                                                                            4-Methoxyphenyl                                      Methyl      Difluoromethoxy                                                                            2-Hydroxyphenyl                                      Methyl      Difluoromethoxy                                                                            4-Chlorophenyl                                       Methyl      Difluoromethoxy                                                                            4-Fluorophenyl                                       Methyl      Difluoromethoxy                                                                            2-Pyridyl                                            Methyl      Difluoromethoxy                                                                            2-Pyrimidinyl                                        Isopropyl   Difluoromethoxy                                                                            2-Methoxyphenyl                                      Isopropyl   Dilfuoromethoxy                                                                            2-Pyrimidinyl                                        4-Fluorophenyl                                                                            Dilfuoromethoxy                                                                            2-Aminophenyl                                        2,4-Difluorophenyl                                                                        Difluoromethoxy                                                                            2-Trifluoromethylphenyl                              Cyclobutyl  Difluoromethoxy                                                                            2-Pyrimidinyl                                        Cycloheptyl Difluoromethoxy                                                                            2-Pyrimidinyl                                        Cyclohexyl  Difluoromethoxy                                                                            2-Pyrimidinyl                                        Methoxy     Difluoromethoxy                                                                            2-Pyrimidinyl                                        2-Fluorocyclopropyl                                                                       Difluoromethoxy                                                                            2-Pyrimidinyl                                        Ethyl       Ethoxy       2-Methoxyphenyl                                      H           Difluoromethoxy                                                                            2-Methoxyphenyl                                      2-Hydroxyethyl                                                                            Difluoromethoxy                                                                            2-Methoxyphenyl                                      2-Acetoxyethyl                                                                            Difluoromethoxy                                                                            2-Methoxyphenyl                                      Carboxymethyl                                                                             Difluoromethoxy                                                                            2-Methoxyphenyl                                      2-Dimethylaminoethyl                                                                      Difluoromethoxy                                                                            2-Methoxyphenyl                                      2-Morpholinoethyl                                                                         Difluoromethoxy                                                                            2-Methoxyphenyl                                      2-Pyridylmethyl                                                                           Difluoromethoxy                                                                            2-Methoxyphenyl                                      Methylamino Difluoromethoxy                                                                            2-Methoxyphenyl                                      2-Hydroxyethyl                                                                            Difluoromethoxy                                                                            2-Pyrimidinyl                                        Methylamino Difluoromethoxy                                                                            2-Pyrimidinyl                                        Vinyl       Difluoromethoxy                                                                            2-Pyrimidinyl                                        2-Prophenyl Difluoromethoxy                                                                            2-Pyrimidinyl                                        Ethynyl     Difluoromethoxy                                                                            2-Pyrimidinyl                                        2-Propynyl  Difluoromethoxy                                                                            2-Pyrimidinyl                                        Cyclopropylmethyl                                                                         Difluoromethoxy                                                                            2-Pyrimidinyl                                        2,4-Difluorophenyl                                                                        Difluoromethoxy                                                                            2-Pyrimidinyl                                        ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                         ##STR18##                                                                    X     R.sup.1     R.sup.2      R.sup.3                                        ______________________________________                                        F     Ethyl       Methoxy      2,4-Dichlorophenyl                             Cl    Ethyl       Methoxy      3,4-Dichlorophenyl                             Cl    Ethyl       Methoxy      1-Naphthyl                                     Cl    Ethyl       Methoxy      2-Naphthyl                                     F     2-Fluoroethyl                                                                             Methoxy      2,4-Dichlorophenyl                             Cl    2-Fluoroethyl                                                                             Methoxy      3,4-Dichlorophenyl                             Cl    2-Fluoroethyl                                                                             Methoxy      1-Naphthyl                                     Cl    2-Fluoroethyl                                                                             Methoxy      2-Naphthyl                                     F     Cyclopropyl Methoxy      2,4-Dichlorophenyl                             Cl    Cyclopropyl Methoxy      3,4-Dichlorophenyl                             Cl    Cyclopropyl Ethoxy       1-Naphthyl                                     Cl    Cyclopropyl Propoxy      2-Naphthyl                                     F     Ethyl       Difluoromethoxy                                                                            2,4-Difluorophenyl                             Cl    Ethyl       Difluoromethoxy                                                                            2,4-Dichlorophenyl                             Cl    Ethyl       Difluoromethoxy                                                                            3,4-Dichlorophenyl                             Cl    Ethyl       Fluoromethoxy                                                                              1-Naphthyl                                     Cl    Ethyl       Trifluoromethoxy                                                                           2-Naphthyl                                     F     2-Fluoroethyl                                                                             Difluoromethoxy                                                                            2,4-Difluorophenyl                             Cl    2-Fluoroethyl                                                                             Difluoromethoxy                                                                            2,4-Dichlorophenyl                             Cl    2-Fluoroethyl                                                                             Difluoromethoxy                                                                            3,4-Dichlorophenyl                             Cl    2-Fluoroethyl                                                                             Fluoromethoxy                                                                              1-Naphthyl                                     Cl    2-Fluoroethyl                                                                             Trifluoromethoxy                                                                           2-Naphthyl                                     F     Cyclopropyl Dilfuoromethoxy                                                                            2,4-Dichlorophenyl                             Cl    Cyclopropyl Difluoromethoxy                                                                            3,4-Dichlorophenyl                             Cl    Cyclopropyl Fluoromethoxy                                                                              1-Naphthyl                                     Cl    Cyclopropyl Trifluoromethoxy                                                                           2-Naphthyl                                     F     Cyclopropyl Fluoromethoxy                                                                              2-Oxazolyl                                     F     Cyclopropyl Difluoromethoxy                                                                            2-Pyridyl                                      F     Isopropyl   Difluoromethoxy                                                                            2-Methoxyphenyl                                ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                         ##STR19##                                                                    R.sup.1 R.sup.2     n     R.sup.3  R.sup.4                                                                             R.sup.5                              ______________________________________                                        Ethyl   Methoxy     2     2-Pyridyl                                                                              H     H                                    2-Fluoro-                                                                             Methoxy     2     2-Pyridyl                                                                              H     H                                    ethyl                                                                         Cyclopropyl                                                                           Methoxy     2     2-Pyridyl                                                                              H     H                                    Ethyl   Methoxy     2     2-Pyrimidinyl                                                                          H     H                                    2-Fluoro-                                                                             Methoxy     2     2-Pyrimidinyl                                                                          H     H                                    ethyl                                                                         Cyclopropyl                                                                           Methoxy     2     2-Pyrimidinyl                                                                          H     H                                    Ethyl   Methoxy     1     2-Pyrimidinyl                                                                          Methyl                                                                              H                                    2-Fluoro-                                                                             Methoxy     1     2-Pyrimidinyl                                                                          Methyl                                                                              H                                    ethyl                                                                         Cyclopropyl                                                                           Methoxy     1     2-Pyrimidinyl                                                                          Methyl                                                                              H                                    Ethyl   Methoxy     1     2-Pyridyl                                                                              Methyl                                                                              H                                    2-Fluoro-                                                                             Methoxy     1     2-Pyridyl                                                                              Methyl                                                                              H                                    ethyl                                                                         Cyclopropyl                                                                           Methoxy     1     2-Pyridyl                                                                              Methyl                                                                              H                                    Ethyl   Difluoromethoxy                                                                           2     2-Pyridyl                                                                              H     H                                    2-Fluoro-                                                                             Difluoromethoxy                                                                           2     2-Pyridyl                                                                              H     H                                    ethyl                                                                         Cyclopropyl                                                                           Difluoromethoxy                                                                           2     2-Pyridyl                                                                              H     H                                    Ethyl   Difluoromethoxy                                                                           2     2-Pyrimidinyl                                                                          H     H                                    2-Fluoro-                                                                             Difluoromethoxy                                                                           2     2-Pyrimidinyl                                                                          H     H                                    ethyl                                                                         Cyclopropyl                                                                           Difluoromethoxy                                                                           2     2-Pyrimidinyl                                                                          H     H                                    Ethyl   Difluoromethoxy                                                                           1     2-Pyrimidinyl                                                                          Methyl                                                                              H                                    2-Fluoro-                                                                             Difluoromethoxy                                                                           1     2-Pyrimidinyl                                                                          Methyl                                                                              H                                    ethyl                                                                         Cyclopropyl                                                                           Difluoromethoxy                                                                           1     2-Pyrimidinyl                                                                          Methyl                                                                              H                                    Ethyl   Difluoromethoxy                                                                           1     2-Pyridyl                                                                              Methyl                                                                              H                                    2-Fluoro-                                                                             Difluoromethoxy                                                                           1     2-Pyridyl                                                                              Methyl                                                                              H                                    ethyl                                                                         Cyclopropyl                                                                           Difluoromethoxy                                                                           1     2-Pyridyl                                                                              Methyl                                                                              H                                    Methyl  Difluoromethoxy                                                                           1     2-Pyrimidinyl                                                                          Methyl                                                                              Methyl                               Ethyl   Difluoromethoxy                                                                           1     2-Pyrimidinyl                                                                          Methyl                                                                              Methyl                               Cyclopropyl                                                                           Difluoromethoxy                                                                           1     2-Pyrimidinyl                                                                          Methyl                                                                              Methyl                               ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                         ##STR20##                                                                    R.sup.1     R.sup.2      R.sup.3                                              ______________________________________                                        Cyclopropyl H            2-Methoxyphenyl                                      Ethyl       H            2-Methoxyphenyl                                      2-Fluorophenyl                                                                            H            3-Methoxyphenyl                                      4-Fluorophenyl                                                                            H            4-Trifluoromethylphenyl                              2,4-Difluorophenyl                                                                        H            3-Aminophenyl                                        Cyclopropyl H            2-Pyridyl                                            Ethyl       H            2-Pyridyl                                            2-Fluoroethyl                                                                             H            2-Pyridyl                                            4-Fluorophenyl                                                                            H            2-Pyridyl                                            Cyclopropyl F            2-Methoxyphenyl                                      Methyl      F            2-Fluorophenyl                                       Ethyl       F            2-Methoxyphenyl                                      2-Fluoroethyl                                                                             F            2-Methoxyphenyl                                      2-Fluoroethyl                                                                             F            2-Pyridyl                                            Cyclopropyl F            2-Pyridyl                                            4-Fluorophenyl                                                                            F            4-Methoxyphenyl                                      2,4-Difluorophenyl                                                                        F            4-Aminophenyl                                        Methyl      Cl           3-Fluorophenyl                                       4-Fluorophenyl                                                                            Cl           2-Nitrophenyl                                        2,4-Difluorophenyl                                                                        Cl           2-Dimethylaminophenyl                                Methyl      Br           4-Fluorophenyl                                       Methyl      Methyl       2-Chlorophenyl                                       4-Fluorophenyl                                                                            Methyl       3-Nitrophenyl                                        2,4-Difluorophenyl                                                                        Methyl       3-Dimethylaminophenyl                                Ethyl       Trifluoromethyl                                                                            2-Pyrimidinyl                                        Cyclopropyl H            2-Pyrimidinyl                                        t-Butyl     H            2-Pyrimidinyl                                        2,4-Difluorophenyl                                                                        H            2-Pyrimidinyl                                        2-Fluoroethyl                                                                             F            2-Pyrimidinyl                                        2-Hydroxyethyl                                                                            F            2-Pyrimidinyl                                        Ethyl       Cl           2-Pyrimidinyl                                        Ethyl       Methyl       2-Pyrimidinyl                                        ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                         ##STR21##                                                                    R.sup.3         R.sup.3                                                       ______________________________________                                        Phenyl          2-Oxazolyl                                                    2-Fluorophenyl  2-Thiazolyl                                                   3-Fluorophenyl  2-Imidazolyl                                                  4-Fluorophenyl  2-Pyridyl                                                     2-Chlorophenyl  6-Methoxy-2-pyridyl                                           3-Chlorophenyl  3-Nitro-2-pyridyl                                             4-Chlorophenyl  4-Amino-2-pyridyl                                             2-Methoxyphenyl 3-Methylamino-2-pyridyl                                       3-Methoxyphenyl 3-Ethylamino-2-pyridyl                                        4-Methoxyphenyl 3-Fluoro-2-pyridyl                                            2-Nitrophenyl   3-Pyridyl                                                     3-Nitrophenyl   4-Pyridyl                                                     4-Nitrophenyl   2-Benzoxazolyl                                                2-Aminophenyl   5-Chloro-2-benzoxazolyl                                       3-Aminophenyl   2-Benzothiazolyl                                              4-Aminophenyl   5-Methyl-2-benzothiazolyl                                     2-Dimethylaminophenyl                                                                         2-Benzimidazolyl                                              3-Dimethylaminophenyl                                                                         2-Pyrimidinyl                                                 4-Dimethylaminophenyl                                                                         5-Chloro-2-pyrimidinyl                                        2-Trifluoromethylphenyl                                                                       4-Methoxy-2-pyrimidinyl                                       3-Trifluoromethylphenyl                                                                       4,6-Dimethoxy-2-pyrimidinyl                                   4-Trifluoromethylphenyl                                                                       4-Pyrimidinyl                                                 2,4-Difluorophenyl                                                                            5-Chloro-6-methyl-4-pyrimidinyl                                               3-Pyridazinyl                                                                 6-Chloro-3-pyridazinyl                                                        2-Pyrazinyl                                                   ______________________________________                                    

                  TABLE 12                                                        ______________________________________                                         ##STR22##                                                                    X      Y         n      R.sup.3      R.sup.4                                  ______________________________________                                        Cl     H         1      2,4-Dichlorophenyl                                                                         H                                        Cl     H         1      3,4-Dichlorophenyl                                                                         H                                        Cl     Amino     1      1-Naphthyl   H                                        Cl     Amino     1      2-Naphthyl   H                                        F      H         2      2-Pyridyl    H                                        F      H         2      2-Pyrimidinyl                                                                              H                                        F      H         1      2-Pyridyl    Methyl                                   F      H         1      2-Pyrimidinyl                                                                              Methyl                                   ______________________________________                                    

                  TABLE 13                                                        ______________________________________                                         ##STR23##                                                                    R.sup.3    G     A        R.sup.3     G   A                                   ______________________________________                                        2-Fluorophenyl                                                                           CH    CH.sub.3 2-Oxazolyl  CH  CH.sub.3                            3-Fluorophenyl                                                                           CH    CH.sub.3 2-Thiazolyl CH  CH.sub.3                            4-Fluorophenyl                                                                           CH    CH.sub.3 2-Imidazolyl                                                                              CH  CH.sub.3                            2-Chlorophenyl                                                                           CH    CH.sub.3 2-Pyridyl   CH  CH.sub.3                            3-Chlorophenyl                                                                           CH    CH.sub.3 6-Methoxy-2-pyridyl                                                                       CH  CH.sub.3                            4-Chlorophenyl                                                                           CH    CH.sub.3 3-Nitro-2-pyridyl                                                                         CH  CH.sub.3                            2-Methoxyphenyl                                                                          CH    CH.sub.3 3-Amino-2-pyridyl                                                                         CH  CH.sub.3                            3-Methoxyphenyl                                                                          CH    CH.sub.3 3-Methylamino-2-                                                                          CH  CH.sub.3                                                      pyridyl                                             4-Methoxyphenyl                                                                          CH    CH.sub.3 3-Ethylamino-2-                                                                           CH  CH.sub.3                                                      pyridyl                                             2-Nitrophenyl                                                                            CH    CH.sub.3 3-Fluoro-2-pyridyl                                                                        CH  CH.sub.3                            3-Nitrophenyl                                                                            CH    CH.sub.3 3-Pyridyl   CH  CH.sub.3                            4-Nitrophenyl                                                                            CH    CH.sub.3 4-Pyridyl   CH  CH.sub.3                            2-Aminophenyl                                                                            CH    CH.sub.3 2-Benzoxazolyl                                                                            CH  CH.sub.3                            3-Aminophenyl                                                                            CH    CH.sub.3 5-Chloro-2- CH  CH.sub.3                                                      benzoxazolyl                                        4-Aminophenyl                                                                            CH    CH.sub.3 2-Benzothiazolyl                                                                          CH  CH.sub.3                            2-Dimethylamino-                                                                         CH    CH.sub.3 5-Methyl-2-benzo-                                                                         CH  CH.sub.3                            phenyl                    thiazolyl                                           3-Dimethylamino-                                                                         CH    CH.sub.3 2-Benzimidazolyl                                                                          CH  CH.sub.3                            phenyl                                                                        4-Dimethylamino-                                                                         CH    CH.sub.3 2-Pyrimidinyl                                                                             CH  CH.sub.3                            phenyl                                                                        2-Trifluoromethyl-                                                                       CH    CH.sub.3 5-Chloro-2-pyrimi-                                                                        CH  CH.sub.3                            phenyl                    dinyl                                               3-Trifluoromethyl-                                                                       CH    CH.sub.3 4-Methoxy-2-pyrimi-                                                                       CH  CH.sub.3                            phenyl                    dinyl                                               4-Trifluoromethyl-                                                                       CH    CH.sub.3 4,6-Dimethoxy-2-                                                                          CH  CH.sub.3                            phenyl                    pyrimidinyl                                         2,4-Difluorophenyl                                                                       CH    CH.sub.3 4-Pyrimidinyl                                                                             CH  CH.sub.3                            2-Pyrimidinyl                                                                            CH    CH.sub.2 Cl                                                                            5-Chloro-6-methyl-4-                                                                      CH  CH.sub.3                                                      pyrimidinyl                                         2-Pyrimidinyl                                                                            CH    CH.sub.2 OH                                                                            3-Pyridazinyl                                                                             CH  CH.sub.3                            2-Pyrimidinyl                                                                            CH    CH.sub.2 OCH.sub.3                                                                     6-Chloro-3-pyrida-                                                                        CH  CH.sub.3                                                      zinyl                                                                         2-Pyrazinyl CH  CH.sub.3                                                      2-Pyrimidinyl                                                                             CH  H                                                             2-Pyrimidinyl                                                                             N   CH.sub.3                            ______________________________________                                    

                  TABLE 14                                                        ______________________________________                                         ##STR24##                                                                    R.sup.3      G       G.sup.1   A      p                                       ______________________________________                                        2-Pyrimidinyl                                                                              CH      S         H      1                                       2-Pyrimidinyl                                                                              CH      S         CH.sub.3                                                                             1                                       2-Pyrimidinyl                                                                              CH      S         CH.sub.2 F                                                                           1                                       2-Pyrimidinyl                                                                              CH      NH        CH.sub.3                                                                             1                                       2-Pyrimidinyl                                                                              CH      NCH.sub.3 CH.sub.3                                                                             1                                       2-Pyrimidinyl                                                                              CH      CH.sub.2  H      1                                       2-Pyrimidinyl                                                                              CH      CH.sub.2  CH.sub.3                                                                             1                                       2-Pyrimidinyl                                                                              CH      CH.sub.2  CH.sub.2 F                                                                           1                                       2-Pyrimidinyl                                                                              CH      CH.sub.2  H      0                                       2-Pyrimidinyl                                                                              CH      CH.sub.2  CH.sub.3                                                                             0                                       2-Pyrimidinyl                                                                              N       CH.sub.2  CH.sub.3                                                                             1                                       2-Pyrimidinyl                                                                              CH      CO        CH.sub.3                                                                             1                                       ______________________________________                                    

                  TABLE 15                                                        ______________________________________                                         ##STR25##                                                                    X      Y         n      R.sup.3      R.sup.4                                  ______________________________________                                        Cl     H         1      2,4-Dichlorophenyl                                                                         H                                        Cl     H         1      3,4-Dichlorophenyl                                                                         H                                        Cl     Amino     1      1-Naphthyl   H                                        Cl     Amino     1      2-Naphthyl   H                                        F      H         2      2-Pyridyl    H                                        F      H         2      2-Pyrimidinyl                                                                              H                                        F      H         1      2-Pyridyl    Methyl                                   F      H         1      2-Pyrimidinyl                                                                              Methyl                                   ______________________________________                                    

                  TABLE 16                                                        ______________________________________                                         ##STR26##                                                                    R.sup.1             R.sup.3                                                   ______________________________________                                        Cyclopropyl         2-Pyridyl                                                 Ethyl               2-Pyridyl                                                 2-Fluoroethyl       2-Pyridyl                                                 4-Fluorophenyl      2-Methyoxyphenyl                                          Ethyl               2-Methyoxyphenyl                                          Ethyl               2-Pyrimidinyl                                             2,4-Difluorophenyl  2-Pyrimidinyl                                             ______________________________________                                    

                  TABLE 17                                                        ______________________________________                                         ##STR27##                                                                    X   Y        Z            R.sup.1                                                                             R.sup.2                                                                              R.sup.3                                ______________________________________                                        H   H        Carboxyl     Ethyl Difluoro-                                                                            2-Pyrimi-                                                              methoxy                                                                              dinyl                                  F   H        5-Tetrazolyl Ethyl Difluoro-                                                                            2-Pyrimi-                                                              methoxy                                                                              dinyl                                  F   F        Carboxyl     Cyclo-                                                                              F      2-Pyrimi-                                                        propyl       dinyl                                  F   H        Ethoxycarbonyl                                                                             Ethyl Difluoro-                                                                            2-Pyrimi-                                                              methoxy                                                                              dinyl                                  F   H        2-Morpholino-                                                                              Ethyl Difluoro-                                                                            2-Pyrimi-                                           ethoxycarbonyl     methoxy                                                                              dinyl                                  F   H        2-Piperidino-                                                                              Ethyl Difluoro-                                                                            2-Pyrimi-                                           ethoxycarbonyl     methoxy                                                                              dinyl                                  F   H        2-(4-methylpiperi-                                                                         Ethyl Difluoro-                                                                            2-Pyrimi-                                           dino)ethoxycarbonyl                                                                              methoxy                                                                              dinyl                                  F   H        2-Morpholino-                                                                              Methyl                                                                              Difluoro-                                                                            2-Methoxy-                                          ethoxycarbonyl     methoxy                                                                              phenyl                                 F   Methyl   Carboxyl     Ethyl H      2-Methoxy-                                                                    phenyl                                 F   Methyl-  Carboxyl     Ethyl Difluoro-                                                                            2-Pyrimi-                                  amino                       methoxy                                                                              dinyl                                  F   Dimethyl-                                                                              Carboxyl     Ethyl Difluoro-                                                                            2-Pyrimi-                                  amino                       methoxy                                                                              dinyl                                  F   Benzyl-  Carboxyl     Ethyl Difluoro-                                                                            2-Pyrimi-                                  amino                       methoxy                                                                              dinyl                                  F   Benzyl-  Carboxyl     Ethyl Difluoro-                                                                            Phenyl                                     amino                       methoxy                                       F   H        Acetoxymethoxy-                                                                            Ethyl Difluoro-                                                                            2-Pyrimi-                                           carbonyl           methoxy                                                                              dinyl                                  ______________________________________                                    

                  TABLE 18                                                        ______________________________________                                         ##STR28##                                                                    R.sup.6      R.sup.7  R.sup.8  m    n'   n"                                   ______________________________________                                        2-Pyrimidinyl                                                                              H        H        0    1    2                                    Phenyl       H        4-OH     0    1    2                                    Phenyl       H        4-OCH.sub.3                                                                            0    1    2                                    2-Pyrimidinyl                                                                              Methyl   H        0    1    2                                    2-Pyrimidinyl                                                                              H        H        1    1    2                                    2-Pyrimidinyl                                                                              Methyl   H        1    1    2                                    2-Pyrimidinyl                                                                              H        H        0    2    2                                    2-Pyrimidinyl                                                                              Methyl   H        0    2    2                                    2-Pyrimidinyl                                                                              H        H        0    1    3                                    2-Pyrimidinyl                                                                              H        H        0    1    1                                    ______________________________________                                    

                  TABLE 19                                                        ______________________________________                                         ##STR29##                                                                    R.sup.2        R.sup.3      T                                                 ______________________________________                                        H              2-Pyrimidinyl                                                                               ##STR30##                                        Methoxy        2-Pyrimidinyl                                                                               ##STR31##                                        Difluoromethoxy                                                                              2-Pyrimidinyl                                                                               ##STR32##                                        Difluoromethoxy                                                                              2-Pyrimidinyl                                                                               ##STR33##                                        Difluoromethoxy                                                                              2-Pyrimidinyl                                                                               ##STR34##                                        Difluoromethoxy                                                                              2-Pyrimidinyl                                                                               ##STR35##                                        ______________________________________                                    

                  TABLE 20                                                        ______________________________________                                         ##STR36##                                                                    R.sup.1   R.sup.2       R.sup.3      W                                        ______________________________________                                        Ethyl     Difluoromethoxy                                                                             2-Pyrimidinyl                                                                              S                                        Ethyl     Methoxy       2-Pyrimidinyl                                                                              S                                        Ethyl     Difluoromethoxy                                                                             2-Pyrimidinyl                                                                              O                                        Ethyl     Methoxy       2-Pyrimidinyl                                                                              O                                        Ethyl     Difluoromethoxy                                                                             2-Pyridyl    S                                        Ethyl     Methoxy       2-Pyridyl    S                                        ______________________________________                                    

Among the above compounds of the present invention, the followingcompounds are preferred:

1-cyclopropyl-6-fluoro-8-difluoromethoxy-7-4-(2-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-6-fluoro-8-difluoromethoxy-7-(4-phenylpiperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-6-fluoro-8-difluoromethoxy-7-4-(4-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

6-fluoro-8-difluoromethoxy-1-methyl-7-4-(2-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

6-fluoro-8-difluoromethoxy-1-methyl-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-(2-acetoxyethyl)-6-fluoro-8-difluoromethoxy-7-4-(2-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

9-fluoro-3-fluoromethyl-10-4-(2-pyrimidinyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid,

2-morpholinoethyl 1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylate,

ethyl 1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylate,

2-piperidinoethyl 1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylate,

2-(4-methylpiperidino)ethyl 1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylateand

2-morpholinoethyl 6-fluoro-8-difluoromethoxy-1-methyl-7-4-(2-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylate,

and 1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid is particularly preferred.

The compounds represented by the above formulae (Ia), (Ib) and (Ic) canbe prepared by Method A shown below.

In the case of the compound represented by the formula (Ia), it can bealso prepared by Method B shown below. ##STR37## wherein R, R¹, Q, T, W,X, Y and Z each have the same meanings as defined above; Hal representsa halogen atom; and L represents a fluorine atom or an acetoxy group.

In Method A, the desired compound of the formula (Ia), (Ib) or (Ic) isprepared by coupling the quinolone derivative (IIIa), (IIIb) or (IIIc)with the cyclic amine derivative (V) in the presence or absence of abase and in the presence or absence of a solvent.

As the solvent to be used in this reaction, there may be preferably usedan aprotic polar solvent such as dimethyl sulfoxide,N,N-dimethylformamide, hexamethylphosphoric triamide andN,N-dimethylacetamide, and in addition, there may be also used ketonessuch as acetone and methyl ethyl ketone; ethers such as diethyl ether,tetrahydrofuran and dioxane; esters such as ethyl acetate; alcohols suchas methanol, ethanol, propanol, isopropanol and butanol; and nitrilessuch as acetonitrile. As the base, there may be exemplified tertiaryamines such as 1,8-diazabicyclo- 5.4.0!-7-undecene, 1,5-diazabicyclo4.3.0!-5-nonene, triethylamine, tributylamine, pyridine, picoline,lutidine and collidine; a metal alkoxide such as sodium methoxide,sodium ethoxide and potassium-t-butoxide; and an inorganic base such assodium carbonate and potassium carbonate.

The amount of the base to be used is preferably an equimolar amount to5-fold moles based on the compound (IIIa), (IIIb) or (IIIc), and whenthe above tertiary amine is used, an extremely excessive amount thereofmay be used as a solvent. The excessive cyclic amine (V) also functionsas a base so that the reaction can proceed smoothly even when other baseis not added. The reaction is carried out in the range of 0° C. to 200°C.

In Method A, the desired compound represented by the formula (Ia) or(Ic) can be also obtained by carrying out the same reaction by not usingthe compound (IIIa) or (IIIc) in which Z is a carboxyl group but using alower alkyl ester compound thereof to prepare a lower alkyl estercompound corresponding to the formula (Ia) or (Ic), and then hydrolyzingthe resulting compound according to a conventional manner.

In Method B, the desired compound of the formula (Ia) is prepared byreacting the boron chelate compound (IVa) of a carboxyquinolone with thecyclic amine (V) by the same method as in Method A to obtain thecompound (Ia'), and then reacting the compound (Ia') in an aqueousalcohol in the presence of a base whereby decomposing the chelate.

As the base to be used for decomposing the chelate in the above MethodB, there may be mentioned an alkali hydroxide such as sodium hydroxideand potassium hydroxide; an alkali carbonate such as sodium carbonateand potassium carbonate; tertiary amines such as 1,8-diazabicyclo5.4.0!-7-undecene, 1,5-diazabicyclo 4.3.0!-5-nonene, triethylamine and4-dimethylaminopyridine; or a metal alkoxide such as sodium methoxide,sodium ethoxide and potassium-t-butoxide.

In the reaction described above, after completion of the reaction, thedesired compound can be obtained by treating the reaction mixtureaccording to a conventional manner, and, if necessary, it can bepurified by a conventional purification means such as recrystallizationand column chromatography.

The compounds of the formulae (Ia), (Ib) and (Ic) thus obtained are madeinto desired salts according to a conventional manner, if necessary.

The compounds of the above formulae (Ia), (Ib) and (Ic) wherein R³ inthe substituent R is an aromatic heterocyclic group can be also preparedby Method C shown below. ##STR38## wherein R⁴, R⁵, R⁷, R⁸, m, n, n', n"and Hal each have the same meanings as defined above; R^(3') and R^(6')represent the aromatic heterocyclic groups mentioned in the descriptionof R³ and R⁶ ; and M represents a formula of (Ma), (Mb) or (Mc),##STR39## wherein R¹, Q, T, W, X, Y and Z each have the same meanings asdefined above.

The reaction of Method C is carried out in the same manner as in MethodA.

The compounds (VI) and (VII) which are used as starting materials inMethod C can be prepared by using the compound (IIIa), (IIIb), (IIIc) or(IVa) as a starting compound and reacting said starting compound in thesame manner as in Method A or Method B by using the cyclic amine (V'-1)or (V'-2) shown below in place of the above cyclic amine (V). ##STR40##wherein R⁴, R⁵, R⁷, R⁸, m, n, n' and n" each have the same meanings asdefined above.

The compound of the above formula (Ia) or (Ic) wherein Z is a5-tetrazolyl group can be also prepared from a corresponding cyanocompound of the formula (IX) or (X), respectively, by Method D shownbelow. ##STR41## wherein R, R¹, Q, T, X and Y each have the samemeanings as defined above.

In Method D, the compound (Ia") or (Ic") is synthesized by reacting thecompound (IX) or (X) with a 1- to 10-fold molar amount, preferably a 1-to 5-fold molar amount of an azide compound in a solvent.

As the azide compound to be used in the reaction, there may bementioned, for example, alkali metal azides such as sodium azide,potassium azide and lithium azide; alkaline earth metal azides such ascalcium azide and magnesium azide; and organic tin azides such astributyltin azide and triphenyltin azide. In said reaction, the azidecompound may be used singly or may be used in combination with, forexample, a Lewis acid such as aluminum chloride, stannic chloride, zincchloride, titanium chloride, tri(butyl)tin chloride and atrifluoroboran-diethyl ether complex; ammonium salts such as ammoniumchloride and tetramethylammonium chloride; sulfonic acids such asmethanesulfonic acid and ethanesulfonic acid; alkali metal chloridessuch as lithium chloride; and amine salts such as triethylaminehydrochloride. As a use example of the above azide compound, there maybe also employed a method in which tri(butyl)tin azide is formed fromtri(butyl)tin chloride and sodium azide in a system, and then providedfor use.

The solvent to be used is not particularly limited so long as it isinactive to the reaction, and may include, for example, aprotic polarsolvents such as N,N-dimethyl-formamide, dimethyl sulfoxide,N-methylpyrrolidone and N,N-dimethylacetamide; ethers such astetrahydrofuran, di-methoxyethane, diethoxyethane and dioxane; aromatichydrocarbons such as benzene, toluene and xylene; and aliphatichydrocarbons such as hexane and petroleum ether.

The reaction temperature is in the range of 0° to 200° C., preferably 0°to 150° C. The reaction time varies depending on the other conditions,but it is generally 1 to 72 hours, preferably 3 to 48 hours.

In the above Method A and Method B, the compounds of the formulae (IIIb)and (IVa), and the compounds of the formulae (IIIa) and (IIIc) in whichZ is a carboxyl group or lower alkyl ester compounds thereof which areused as starting materials, can be easily prepared by usingcorresponding starting materials suitably according to a known method,for example, methods described in Japanese Provisional PatentPublications No. 30964/1981, No. 74667/1983 (which corresponds to U.S.Pat. No. 4,620,007, U.S. Pat. No. 4,670,444 and U.S. Pat. No. 5,077,429,hereinafter the same), U.S. Pat. No. 90511/1983, U.S. Pat. No.103393/1983 (U.S. Pat. No. 4,426,381), U.S. Pat. No. 67290/1984, U.S.Pat. No. 76091/1984, U.S. Pat. No. 56959/1985 (U.S. Pat. No. 4,730,000),U.S. Pat. No. 126271/1985, U.S. Pat. No. 163866/1985 (U.S. Pat. No.4,774,246), U.S. Pat. No. 172981/1985, U.S. Pat. No. 174786/1985 (U.S.Pat. No. 4,616,019), U.S. Pat. No. 452/1987 (U.S. Pat. No. 4,762,831,U.S. Pat. No. 4,859,773 and U.S. Pat. No. 4,958,045), U.S. Pat. No.53987/1987 (U.S. Pat. No. 4,720,495), U.S. Pat. No. 155282/1987, U.S.Pat. No. 187472/1987 (U.S. Pat. No. 4,767,762), U.S. Pat. No.228063/1987, U.S. Pat. No. 132891/1988 (U.S. Pat. No. 4,801,584), U.S.Pat. No. 198664/1988 (U.S. Pat. No. 4,997,943), U.S. Pat. No.264461/1988 (U.S. Pat. No. 4,855,292 and U.S. Pat. No. 4,935,420), U.S.Pat. No. 297366/1988, U.S. Pat. No. 124873/1990 (U.S. Pat. No.5,073,556), U.S. Pat. No. 191257/1990 (U.S. Pat. No. 4,971,970), U.S.Pat. No. 231476/1990 (U.S. Pat. No. 5,073,556) and U.S. Pat. No.209367/1991.

Among the compound of the formula (IIIa) or (IIIc), the compound of theformula (IIIa') or (IIIc') wherein Z is a 5-tetrazolyl group can beprepared from a corresponding cyano compound by Method E shown below.##STR42## wherein R¹, Q, T, X, Y and Hal each have the same meanings asdefined above.

Method E is carried out in the same manner as in Method D. In Method E,the compounds of the formulae (IIIa") and (IIIc") which are used asstarting compounds can be prepared by using various starting materialsin which a part corresponding to a carboxyl group is a cyano groupaccording to the methods described in the publications enumerated aboutthe compounds of the above formulae (IIIa) and (IIIc) wherein Z is acarboxyl group.

In the compounds represented by the above formulae (Ia), (Ib) and (Ic)prepared as described above, optical isomers or geometrical (cis ortrans) isomers may exist. In that case, optical isomers or geometricalisomers of the corresponding desired compounds of the formulae (Ia),(Ib) and (Ic) can be obtained by carrying out the above reaction usingoptically divided or separated starting compounds, if desired. Also, therespective stereoisomers can be also obtained by processing a mixture ofoptical isomers or geometrical isomers of the compounds represented bythe formulae (Ia), (Ib) and (Ic) according to a conventional opticaldivision method or separation method.

When the compounds represented by the above formulae (Ia), (Ib) and (Ic)have carboxyl groups in their molecules, the carboxyl groups may beprotected to form esters as described above, and the ester formationreaction is carried out by using a corresponding carboxyl compound and acorresponding alcohol according to a conventional method (e.g. adehydration condensation method by an acid catalyst, a method through anacid halide or a dehydration condensation method using a carbodiimide).

The compounds represented by the formulae (Ia), (Ib) and (Ic) are usefulas an AIDS curing agent. The compounds of the present invention may beadministered by any suitable route commonly used for antiviralcompounds, and may be formulated in admixture with conventionaladditives or adjuvants for this purpose. For example, for oraladministration, there may be formulated as tablets, capsules, granules,powders or syrup; whilst for parenteral administration, they may beformulated as injections or suppositories.

Where the compounds of the present invention are to be administered byinjection, they may be administered by a conventional route such as, forexample, by the intravascular, intraperitoneal, intramuscular orsubcutaneous routes.

Injectable formulations will generally comprise a pharmaceuticallyacceptable carrier and, optionally, one or more additional antiviralcompounds and, if necessary, substances to render the injection isotonicwith the body fluids, as well as other ingredients as may be required,such as emulsifiers.

Injections may be sub-divided for separate administration, whethersimultaneously or over a period of time, suitably weeks.

The pharmaceutical preparations of the present invention can be preparedby any conventional means, using such additives as vehicles, binders,disintegrators, lubricants, stabilizers and corrigents.

Although the dosage may vary, depending on the age, body weight andsymptoms of the patient, for an adult human patient, a suitable dailydosage may be from about 100 to about 2000 mg, or from about 1 to about25 mg/kg body weight, per day, which may be administered as a singledose or divided into several doses. When several-fold doses (calculatedbased on weight) of the above dose of the compounds of the formulae(Ia), (Ib) and (Ic) were orally administered to rats, toxicities thereofwere not recognized.

EXAMPLES

The present invention will now be illustrated in more detail withreference to the accompanying Examples and Reference examples.

Example 1 Synthesis of 1-cyclopropyl-6-fluoro-8-difluoromethoxy-7-4-(2-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.hydrochloride ##STR43##

In 20 ml of pyridine were dissolved 1.66 g (0.005 mole) of1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 2.4 g (0.0125 mole) of 1-(2-methoxyphenyl)piperazine, and themixture was stirred at 105° to 110° C. for 3 hours. Then, the solventwas removed under reduced pressure, and the residue was subjected tosilica gel column chromatography (the eluent used was a mixture ofchloroform:methanol=9.5:0.5) to obtain 1.33 g of of free title compound.Next, 1.33 g of the free compound was dissolved in 100 ml of a mixtureof chloroform and methanol (4:1), and 2 ml of conc. hydrochloric acidwas added thereto. The mixture was concentrated under reduced pressure,and the residue was washed with a mixture of methanol and ethanol (4:1),and dried to obtain 1.08 g of the title compound as white powder.

Melting point: 223° to 225° C.

NMR(DMSO-d₆, δ): 1.04˜1.07 (2H, m), 1.16˜1.17 (2H, m), 3.30 (4H, br.s),3.47 (4H, br.s), 3.86 (3H, s), 4.09˜4.12 (1H, m), 6.90˜7.27 (5H, m),7.95˜7.98 (1H, d, J=12.1Hz), 8.79 (1H, s)

MS spectrum (CI): m/e 504 (M⁺ +1)

Examples 2 to 62

Using a similar method to Example 1, but using appropriate startingmaterials, the compounds shown in Table 21 were synthesized.

                  TABLE 21                                                        ______________________________________                                         ##STR44##                                                                    Ex-                                                                           am-                                                                           ple  Y       R.sup.1   R.sup.2                                                                              R.sup.3   m.p. (°C.)                     ______________________________________                                        2    H       Cyclo-    Difluoro-                                                                            Phenyl    209 to 211                                         propyl    methoxy                                                3    H       Cyclo-    Difluoro-                                                                            2-Chlorophenyl                                                                          281 to 284                                         propyl    methoxy                                                4    H       Cyclo-    Difluoro-                                                                            3-Chlorophenyl                                                                          201 to 203                                         propyl    methoxy          (HCl salt)                            5    H       Cyclo-    Difluoro-                                                                            4-Chlorophenyl                                                                          263 to 265                                         propyl    methoxy          (1/2H.sub.2 O                                                                 adduct)                               6    H       Cyclo-    Difluoro-                                                                            4-Fluorophenyl                                                                          224 to 226                                         propyl    methoxy          (HCl salt)                            7    H       Cyclo-    Difluoro-                                                                            3-Methoxyphenyl                                                                         209 to 212                                         propyl    methoxy                                                8    H       Cyclo-    Difluoro-                                                                            4-Methoxyphenyl                                                                         253 to 255                                         propyl    methoxy                                                9    H       Cyclo-    Difluoro-                                                                            4-Nitrophenyl                                                                           278 to 283                                         propyl    methoxy                                                10   H       Cyclo-    Difluoro-                                                                            4-Aminophenyl                                                                           255 to 260                                         propyl    methoxy          (H.sub.2 O                                                                    adduct)                               11   H       Cyclo-    Difluoro-                                                                            4-Dimethyl-                                                                             265 to 271                                         propyl    methoxy                                                                              aminophenyl                                                                             (decom-                                                                       posed)                                12   H       Cyclo-    Difluoro-                                                                            4-Trifluoro-                                                                            224 to 226                                         propyl    methoxy                                                                              methylphenyl                                                                            (1/2H.sub.2 O                                                                 adduct)                               13   H       Cyclo-    Difluoro-                                                                            2-Pyridyl 230 to 232                                         propyl    methoxy          (HCl salt)                            14   H       Cyclo-    Difluoro-                                                                            6-Methoxy-2-                                                                            209 to 212                                         propyl    methoxy                                                                              pyridyl   (1/2H.sub.2 O                                                                 adduct)                               15   H       Cyclo-    Difluoro-                                                                            4-Amino-2-                                                                              238 to 244                                         propyl    methoxy                                                                              pyridyl   (HCl salt ·                                                          1/2H.sub.2 O                                                                  adduct)                               16   H       Cyclo-    Difluoro-                                                                            3-Ethylamino-                                                                           232 to 234                                         propyl    methoxy                                                                              2-pyridyl                                       17   H       Cyclo-    Difluoro-                                                                            3-Nitro-2-                                                                              233 to 237                                         propyl    methoxy                                                                              pyridyl                                         18   H       Cyclo-    Difluoro-                                                                            2-Pyrimidinyl                                                                           264 to 266                                         propyl    methoxy                                                19   H       Cyclo-    Difluoro-                                                                            5-Chloro-2-                                                                             258 to 260                                         propyl    methoxy                                                                              pyrimidinyl                                                                             (1/2H.sub.2 O                                                                 adduct)                               20   H       Cyclo-    Difluoro-                                                                            4,6-Dimethoxy-                                                                          291 to 293                                         propyl    methoxy                                                                              2-pyrimidinyl                                   21   H       Cyclo-    Difluoro-                                                                            2-Benzoxazolyl                                                                          269 to 272                                         propyl    methoxy                                                22   Amino   Cyclo-    Difluoro-                                                                            2-Pyridyl 288 to 290                                         propyl    methoxy          (1/2H.sub.2 O                                                                 adduct)                               23   H       Methyl    Difluoro-                                                                            2-Methoxyphenyl                                                                         238 to 239                                                   methoxy          (1/2H.sub.2 O                                                                 adduct)                               24   H       Methyl    Difluoro-                                                                            2-Pyrimidinyl                                                                           272 to 274                                                   methoxy                                                25   H       Isopropyl Difluoro-                                                                            2-Methoxyphenyl                                                                         192 to 196                                                   methoxy                                                26   H       Isopropyl Difluoro-                                                                            2-Pyrimidinyl                                                                           278 to 281                                                   methoxy          (1/2H.sub.2 O                                                                 adduct)                               27   H       2-Fluoro- F      2-Methoxyphenyl                                                                         248 to 250                                         ethyl                                                            28   H       Ethyl     Difluoro-                                                                            2-Methylphenyl                                                                          262 to 264                                                   methoxy                                                29   Amino   Isopropyl Difluoro-                                                                            2-Methoxyphenyl                                                                         232 to 233                                                   methoxy                                                30   H       Ethyl     Difluoro-                                                                            2-Ethoxyphenyl                                                                          186 to 188                                                   methoxy                                                31   H       Ethyl     Difluoro-                                                                            2-Thiazolyl                                                                             242 to 244                                                   methoxy                                                32   H       Ethyl     Difluoro-                                                                            2-Pyridyl 251 to 253                                                   methoxy                                                33   H       Ethyl     Difluoro-                                                                            3-Nitro-2-                                                                              218 to 219                                                   methoxy                                                                              pyridyl   (HCl salt ·                                                          1/2H.sub.2 O                                                                  adduct)                               34   H       Ethyl     Difluoro-                                                                            5-Chloro-2-                                                                             285 to 288                                                   methoxy                                                                              pyrimidinyl                                     35   H       Ethyl     Difluoro-                                                                            6-Ethyl-2-                                                                              197 to 201                                                   methoxy                                                                              pyrimidinyl                                     36   H       Ethyl     Difluoro-                                                                            6-Chloro-4-                                                                             224 to 226                                                   methoxy                                                                              pyrimidinyl                                     37   H       Ethyl     Difluoro-                                                                            2-Pyrazinyl                                                                             257 to 260                                                   methoxy                                                38   H       2-Fluoro- Difluoro-                                                                            2-Methoxyphenyl                                                                         230 to 231                                         ethyl     methoxy                                                39   H       2-Fluoro- Difluoro-                                                                            2-Pyrimidinyl                                                                           264 to 266                                         ethyl     methoxy                                                40   H       Methyl    Difluoro-                                                                            3-Methoxyphenyl                                                                         171 to 172                                                   methoxy                                                41   H       Methyl    Difluoro-                                                                            4-Methoxyphenyl                                                                         255 to 257                                                   methoxy                                                42   H       Methyl    Difluoro-                                                                            4-Fluorophenyl                                                                          270 to 272                                                   methoxy                                                43   H       Methyl    Difluoro-                                                                            2-Pyridyl 254 to 255                                                   methoxy                                                44   H       H         Difluoro-                                                                            2-Methoxyphenyl                                                                         254 to 256                                                   methoxy                                                45   H       2-Hydroxy-                                                                              Difluoro-                                                                            2-Methoxyphenyl                                                                         237 to 241                                         ethyl     methoxy                                                46   H       2-Acetoxy-                                                                              Difluoro-                                                                            2-Methoxyphenyl                                                                         209 to 211                                         ethyl     methoxy                                                47   H       Carboxy-  Difluoro-                                                                            2-Methoxyphenyl                                                                         231 to 232                                         methyl    methoxy                                                48   H       2-Dimethyl-                                                                             Difluoro-                                                                            2-Methoxyphenyl                                                                         236 to 237                                         aminoethyl                                                                              methoxy                                                49   H       2-Morpho- Difluoro-                                                                            2-Methoxyphenyl                                                                         215 to 217                                         linoethyl methoxy                                                50   H       2-Pyridyl-                                                                              Difluoro-                                                                            2-Methoxyphenyl                                                                         237 to 239                                         methyl    methoxy                                                51   H       Methylamino                                                                             Difluoro-                                                                            2-Methoxyphenyl                                                                         234 to 236                                                   methoxy                                                52   H       2-Hydroxy-                                                                              Difluoro-                                                                            2-Pyrimidinyl                                                                           254 to 256                                         ethyl     methoxy                                                53   H       Methylamino                                                                             Difluoro-                                                                            2-Pyrimidinyl                                                                           231 to 233                                                   methoxy                                                54   H       2-Hydroxy-                                                                              F      2-Pyrimidinyl                                                                           239 to 241                                         ethyl                                                            55   H       Ethyl     Cl     2-Pyrimidinyl                                                                           230 to 231                                                                    (1/2H.sub.2 O                                                                 adduct)                               56   F       Cyclopropyl                                                                             F      2-Pyrimidinyl                                                                           255 to 257                            57   H       2-Propenyl                                                                              Difluoro-                                                                            2-Pyrimidinyl                                                                           255 to 256                                                   methoxy          (1/2H.sub.2 O                                                                 adduct)                               58   H       2-Propynyl                                                                              Difluoro-                                                                            2-Pyrimidinyl                                                                           254 to 255                                                   methoxy                                                59   H       Ethyl     Methyl 2-Pyrimidinyl                                                                           270 to 272                                                                    (1/2H.sub.2 O                                                                 adduct)                               60   H       2,4-Diflu-                                                                              Difluoro-                                                                            2-Pyrimidinyl                                                                           188 to 190                                         orophenyl methoxy                                                61   Methyl  Ethyl     H      2-Methoxyphenyl                                                                         242 to 243                            62   H       Ethyl     Difluoro-                                                                            4-Pyrimidinyl                                                                           238 to 240                                                   methoxy                                                ______________________________________                                    

example 63 Synthesis of 1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR45##

To a suspension of 5.0 g (0.016 mole) of1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 20 ml of methyl isobutyl ketone was added 4.54 g (0.032 mole)of boron trifluoride.diethyl ether complex and the mixture was refluxedby heating for 6 hours while stirring. The reaction mixture was left tostand for cooling and, precipitated crystals were collected byfiltration and washed with ether and chloroform to obtain 32 g of1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.BF₂ chelate compound as pale pink crystals.

To 5 ml of dimethyl sulfoxide were added 0.5 g (0.00136 mole) of thethus obtained chelate compound, 1.3 g (0.0068 mole) of1-(2-methoxyphenyl)piperazine and 2 ml of triethylamine, and the mixturewas stirred at room temperature for 5 hours and then left to standovernight. Water was added to the reaction mixture, and the yellowcrystals which precipitated were collected by filtration and washed withwater. The crystals were dissolved in 100 ml of 80% methanol containing2.5 ml of triethylamine, and the solution was refluxed by heating for 12hours. Then, the solvent was removed under reduced pressure, and theresidue was washed with a mixed solvent of ethanol and water, and driedto obtain 0.5 g of the title compound as a pale red powder.

Melting point: 219° to 222° C.

NMR(DMSO-d₆, δ): 1.28 (3H, t, J=7.0 Hz), 3.11 (4H, br.s), 3.47 (4H,br.s), 3.81 (3H, s), 4.74 (2H, q, J=7.0 Hz), 6.92˜7.32 (5H, m),8.01˜8.04 (1H, d, J=12.1Hz), 8.96 (1H, s)

MS spectrum (CI): m/e 492 (M⁺ +1)

Examples 64 to 89

By the same method as in Example 63, compounds shown in Table 22 andTable 23 were synthesized.

                  TABLE 22                                                        ______________________________________                                         ##STR46##                                                                    Exam-                                                                         ple   R.sup.1   R.sup.2  R.sup.3 n   m.p. (°C.)                        ______________________________________                                        64    Cyclopropyl                                                                             Methoxy  2-Methoxy-                                                                            1   201 to 203                                                        phenyl      (H.sub.2 O adduct)                       65    Cyclopropyl                                                                             Methoxy  2-Pyridyl                                                                             1   209 to 213 (HCl                                                               salt.H.sub.2 O adduct)                   66    Cyclopropyl                                                                             Methoxy  2-Pyrimi-                                                                             1   262 to 264                                                        dinyl                                                67    Ethyl     Difluoro-                                                                              2-Pyrimi-                                                                             1   251 to 253                                               methoxy  dinyl                                                68    Ethyl     Difluoro-                                                                              4-Methoxy-                                                                            1   247 to 249                                               methoxy  phenyl                                               69    Ethyl     Methoxy  2-Methoxy-                                                                            1   245 to 247                                                        phenyl                                               70    2-Fluoro- Methoxy  2-Methoxy-                                                                            1   239 to 241                                     ethyl              phenyl                                               71    Cyclopropyl                                                                             F        2-Methoxy-                                                                            1   207 to 209                                                        phenyl                                               72    Cyclopropyl                                                                             H        2-Methoxy-                                                                            1   227 to 229                                                        phenyl      (1/2H.sub.2 O adduct)                    73    Cyclopropyl                                                                             F        2-Pyridyl                                                                             1   238 to 241                                                                    (HCl salt)                               74    Ethyl     F        2-Methoxy-                                                                            1   221 to 223                                                        phenyl      (1/2H.sub.2 O adduct)                    75    Ethyl     H        2-Methoxy-                                                                            1   208 to 209                                                        phenyl      (1/4H.sub.2 O adduct)                    76    4-Fluoro- H        2-Pyridyl                                                                             1   >300                                           phenyl                                                                  77    Cyclopropyl                                                                             Difluoro-                                                                              2-Pyrimi-                                                                             2   279 to 282                                               methoxy  dinyl                                                78    Ethyl     Ethoxy   2-Methoxy-                                                                            1   223 to 225                                                        phenyl                                               79    Ethyl     Difluoro-                                                                              2-Pyrimi-                                                                             2   246 to 248                                               methoxy  dinyl                                                80    Cyclopropyl                                                                             H        2-Pyrimi-                                                                             1   296 to 298                                                        dinyl       (1/2H.sub.2 O adduct)                    81    2,4-Difluoro-                                                                           H        2-Pyrimi-                                                                             1   >300                                           phenyl             dinyl       (1/2H.sub.2 O adduct)                    82    2-Fluoro- F        2-Pyrimi-                                                                             1   260 to 262                                     ethyl              dinyl                                                83    Ethyl     Difluoro-                                                                              2-Pyrimi-                                                                             1   252 to 255                                               methoxy  dinyl       (HCl salt)                               ______________________________________                                    

                  TABLE 23                                                        ______________________________________                                         ##STR47##                                                                    Exam-                                                                         ple   A        G       R.sup.3   m.p. (°C.)                            ______________________________________                                        84    CH.sub.3 >CH     2-Methoxy-                                                                              262 to 264                                                          phenyl                                                 85    CH.sub.3 >CH     2-Pyridyl 267 to 272                                                                    (1/2H.sub.2 O adduct)                        86    CH.sub.2 F                                                                             >CH     2-Pyridyl 272 to 273 (decom-                                                            posed) (HCl salt.H.sub.2 O                                                    adduct)                                      87    CH.sub.2 F                                                                             >CH     2-Pyrimidinyl                                                                           290 to 299                                   88    H        >CH     2-Pyrimidinyl                                                                           289 to 298 (decom-                                                            posed) (HCl salt.H.sub.2 O                                                    adduct)                                      89    CH.sub.3 >N      2-Pyrimidinyl                                                                           >300                                         ______________________________________                                    

Example 90 Synthesis of 6-fluoro-1-(4-fluorophenyl)-7-4-(2-methoxyphenyl)piperazin-1-yl!-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid ##STR48##

In 40 ml of ethanol was dissolved 0.81 g (0.0042 mole) of1-(2-methoxyphenyl)piperazine, and to the solution was added gradually1.02 g (0.0028 mole) of ethyl7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3carboxylateat 30° C. while stirring. After completion of the addition, the mixturewas reacted at the same temperature for 4 hours. After the reactionmixture was cooled, crystals precipitated were collected by filtrationand washed with ethanol. To the crystals were added 12 ml of a 6Nhydrochloric acid aqueous solution, and the mixture was refluxed byheating for 6 hours. After cooling, the reaction mixture was adjusted topH 8.5 with a 1N sodium hydroxide aqueous solution, and crystalsprecipitated were collected by filtration and applied to silica gelcolumn chromatography (the eluent used was a mixture ofchloroform:methanol=9.5:0.5) to obtain 0.87 g of the title compound asslightly yellow powder.

Melting point: 272° to 273° C.

NMR(DMSO-d₆, δ): 2.97 (4H, br.s), 3.71 (4H, br.s), 3.80 (3H, s),6.86˜7.70 (8H, m), 8.17˜8.20 (1H, d, J=13.6Hz), 8.70 (1H, s), 15.13 (1H,s)

MS spectrum (CI): m/e 493 (M⁺ +1)

examples 91 to 93

By the same method as in Example 90, compounds shown in Table 24 weresynthesized.

                  TABLE 24                                                        ______________________________________                                         ##STR49##                                                                    Example R.sup.1       R.sup.3      m.p. (°C.)                          ______________________________________                                        91      Ethyl         2-Methoxyphenyl                                                                            218 to 220                                 92      Ethyl         2-Pyrimidinyl                                                                              296 to 298                                 93      2,4-Difluorophenyl                                                                          2-Pyrimidinyl                                                                              271 to 272                                 ______________________________________                                    

Example 94 Synthesis of 1-ethyl-6-fluoro-8-difluoromethoxy-7-3-methyl-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR50##

In 60 ml of pyridine were dissolved 3.19 g (0.01 mole) of1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 3.0 g (0.03 mole) of 2-methylpiperazine, and the mixture wasstirred at 105° to 110° C. for 2 hours. Then, the solvent was removedunder reduced pressure. Water was added to the residue, and crystalsprecipitated were collected by filtration, washed with water andethanol, and dried to obtain 3.23 g of1-ethyl-6-fluoro-8-difluoromethoxy-7-(3-methylpiperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid as pale yellow powder.

To 20 ml of N,N-dimethylformamide were added 1.6 g (0.004 mole) of thepowder, 0.9 g (0.008 mole) of 2-chloropyrimidine and 0.81 g (0.008 mole)of triethylamine, and the mixture was stirred at 130° C. for 15 hours.Then, the solvent was removed under reduced pressure. Ethanol was addedto the residue, and crystals precipitated were collected by filtrationand applied to silica gel column chromatography (the eluent used was amixture of chloroform:methanol=9.5:0.5) to obtain 0.34 g of the titlecompound as pale yellow powder.

Melting point: 219° to 221° C.

MS spectrum (CI): m/e 478 (M⁺ +1)

Elemental analysis (%): in terms of C₂₂ H₂₂ F₃ N₅ O₄ Calculated: C:55.35, H: 4.64, N: 14.67 Found: C: 55.41, H: 4.56, N: 14.65

Examples 95 to 97

Using a similar method to Example 94, but using appropriate startingmaterials, the compounds shown in Table 25 were synthesized.

                  TABLE 25                                                        ______________________________________                                         ##STR51##                                                                    Example                                                                              R.sup.1 R.sup.2   R.sup.3  R.sup.4                                                                             m.p. (°C.)                     ______________________________________                                        95     t-Butyl H         2-Pyrimidinyl                                                                          H     276 to 278                            96     Ethyl   Difluoro- 2-Pyrimidinyl                                                                          H     252 to 254                                           methoxy                                                        (The compound is the same compound as that of Example 67                      but prepared by a different method.)                                          97     Cyclo-  Methoxy   2-Pyrimidinyl                                                                          Methyl                                                                              235 to 237                                   propyl                                                                 ______________________________________                                    

Example 98 Synthesis of 1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-3-(5-tetrazolyl)-1,4-dihydro-4-oxoquinoline##STR52##

In the same manner as in Example 1, 4.85 g of3-cyano-1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinolineand 9.49 g of 1-(2-pyrimidinyl)piperazine to obtain 4.2 g of3-cyano-1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline as a paleyellow powder.

Melting point: 286° to 290° C. (decomposed)

To 25 ml of xylene were added 0.5 g (0.0011 mole) of3-cyano-1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline obtained asdescribed above, 0.21 g of (0.0033 mole) of sodium azide and 1.07 g(0.0033 mole) of tributyltin chloride, and the mixture was stirred underreflux by heating for 9 hours. After the mixture was cooled to roomtemperature, 7 ml of a 1N hydrochloric acid aqueous solution was addedthereto, and the mixture was stirred. Then, crystals precipitated werecollected by filtration, washed with ethanol and toluene, and applied tosilica gel column chromatography (the eluent used was a mixture ofchloroform:methanol=9:1) to obtain 0.37 g of the title compound as paleyellow powder.

Melting point: 265° to 268° C.

MS spectrum (CI): m/e 488 (M⁺ +1)

Elemental analysis (%): in terms of C₂₁ H₂₀ F₃ N₉ O₂.1/2H₂ O Calculated:C: 50.81, H: 4.06, N: 25.39 Found: C: 50.96, H: 4.16, N: 25.58

Example 99 Synthesis of 1-ethyl-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR53##

The same reaction as in Example 1 was carried out by using1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 1-(2-pyrimidinyl)piperazine to obtain the title compound aswhite powder.

Melting point: >300° C.

MS spectrum (CI): m/e 446 (M⁺ +1)

Elemental analysis (%): in terms of C₂₁ H₂₁ F₂ N₅ O₄ Calculated: C:56.63, H: 4.75, N: 15.72 Found: C: 56.70, H: 4.62, N: 15.34

Example 100 Synthesis of 6-fluoro-1-methyl-4-oxo-7-4-(2-pyrimidinyl)piperazin-1-yl!-1H,4H- 1,3!thiazeto3,2-a!quinoline-3-carboxylic acid ##STR54##

To 16 ml of N,N-dimethylformamide were added 2.0 g (0.0064 mole) ofethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H- 1,3!-thiazeto3,2-a!quinoline-3-carboxylate, 3.0 g (0.0129 mole) of1-(2-pyrimidinyl)piperazine dihydrochloride and 3.9 g (0.0256 mole) of1,8-diazabicyclo 5.4.0!-7-undecene, and the mixture was stirred at roomtemperature for 5 days. The reaction mixture was added to water, andcrystals precipitated were collected by filtration, washed with waterand dried to obtain 2.8 g of ethyl 6-fluoro-1-methyl-4-oxo-7-4-(2-pyrimidinyl)piperazin-1-yl!-1H,4H- 1,3!thiazeto3,2-a!quinoline-3-carboxylate as pale yellow powder.

To 0.8 g (0.0018 mole) of the powder were added 5 ml of methanol, 1 mlof dioxane, 1 ml of water and 7 ml of a 1N sodium hydroxide solution,and the mixture was stirred at room temperature for 3 days. The reactionmixture was adjusted to pH 7.2 by adding a diluted acetic acid aqueoussolution, and crystals precipitated were collected by filtration andapplied to silica gel column chromatography (the eluent used was amixture of chloroform:methanol=20:1) to obtain 0.22 g of the titlecompound as slightly yellow powder.

Melting point: 266° to 268° C. (decomposed)

MS spectrum (CI): m/e 428 (M⁺ +1)

Elemental analysis (%): in terms of C₂₀ H₁₈ FN₅ O₃ S.1/2H₂ O Calculated:C: 55.04, H: 4.39, N: 16.05 Found: C: 54.85, H: 4.19, N: 15.92

example 101 Synthesis of 1-ethyl-6-fluoro-8-difluoromethoxy-7-(4-hydroxy-3-phenylamino)pyrrolidin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR55##

To 20 ml of pyridine were added 0.9 g (0.0028 mole) of1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, 1.52 g (0.0071 mole) of (4-hydroxy-3-phenylamino)pyrrolidinehydrochloride and 1.6 g (0.0142 mole) of triethylenediamine, and themixture was stirred at room temperature for 30 minutes, followed bystirring at 105° to 110° C. for 3 hours. Then, the solvent was removedunder reduced pressure. Water was added to the residue, and crystalsprecipitated were collected by filtration, washed with ethanol andapplied to silica gel column chromatography (the eluent used was amixture of chloroform:methanol=9.5:0.5) to obtain 0.71 g of the titlecompound as slightly yellowish white powder.

Melting point: 233° to 235° C.

MS spectrum (CI): m/e 478 (M⁺ +1)

Elemental analysis (%): in terms of C₂₃ H₂₂ F₃ N₃ O₅ Calculated: C:57.86, H: 4.64, N: 8.80 Found: C: 57.83, H: 4.59, N: 8.80

Examples 102 to 103

Using a similar method to Example 101, but using appropriate startingmaterials, the compounds shown in Table 26 were synthesized.

                  TABLE 26                                                        ______________________________________                                         ##STR56##                                                                    Example                                                                              R.sup.1 R.sup.2  R.sup.6 R.sup.8 m.p. (°C.)                     ______________________________________                                        102    Ethyl   Difluoro-                                                                              2-Pyrimi-                                                                             H       223 to 225                                           methoxy  dinyl                                                 103    Ethyl   Difluoro-                                                                              Phenyl  Methoxy 209 to 211                                           methoxy                                                        ______________________________________                                    

Example 104 Synthesis of 2-morpholinoethyl1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylate##STR57##

In 3 l of methylene chloride were added 58.94 g (0.127 mole) of1-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, 25.05 g (0.191 mole) of 4-(2-hydroxyethyl)morpholine, 23.3 g(0.191 mole) of 4-dimethylaminopyridine and 48.8 g (0.254 mole) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and themixture was stirred at room temperature for 4 days. Then, the solventwas removed under reduced pressure. The residue was dissolved inchloroform, washed with a 1N hydrochloric acid aqueous solution, washedwith water and dried. The solvent was removed under reduced pressure,and the residue was applied to silica gel column chromatography (theeluent used was a mixture of chloroform: methanol: 28% aqueousammonia=40:9:1) to obtain 50.25 g of the title compound as slightlyyellowish white powder.

Melting point: 162° to 164° C.

MS spectrum (CI): m/e 577 (M⁺ +1)

Elemental analysis (%): in terms of C₂₇ H₃₁ F₃ N₆ O₅ 1/2H₂ O Calculated:C: 55.38, H: 5.34, N: 14.35 Found: C: 55.06, H: 5.20, N: 14.26

Examples 105 to 108

Using a similar method to Example 104, but using appropriate startingmaterials, the compounds shown in Table 27 were synthesized.

                  TABLE 27                                                        ______________________________________                                         ##STR58##                                                                    Exam-                                                                         ple    R.sup.1  R.sup.3   Z           m.p. (°C.)                       ______________________________________                                        105    Ethyl    2-Pyrimi- Ethoxycarbonyl                                                                            138 to 141                                              dinyl                                                         106    Ethyl    2-Pyrimi- 2-Piperidinoethoxy-                                                                       140 to 143                                              dinyl     carbonyl                                            107    Ethyl    2-Pyrimi- 2-(4-methylpiperi-                                                                        186 to 188                                              dinyl     dino)ethoxycarbonyl                                 108    Methyl   2-Methoxy-                                                                              2-Morpholinoethoxy-                                                                       192 to 193                                              phenyl    carbonyl                                            ______________________________________                                    

Example 109 Synthesis of 9-ethyl-6-fluoro-8-difluoromethoxy-7-4-(2-pyrimidinyl)piperazin-1-yl!-2,3,4,9-tetrahydroisothiazolo-5,4-b!quinolin-3,4-dione ##STR59##

The same reaction as in Example 1 was carried out by using mg (1.44mmole) of9-ethyl-6,7-difluoro-8-difluoromethoxy-2,3,4,9-tetrahydroisothiazolo5,4-b!quinolin-3,4-dione and 1.9 g (11.5 mmole) of1-(2-pyrimidinyl)piperazine to obtain 10 mg of the title compound aspale yellow powder.

Melting point: 259° to 262° C.

MS spectrum (CI): m/e 493 (M⁺ +1)

Elemental analysis (%): in terms of C₂₁ H₁₉ F₃ N₆ O₃ S.1/2H₂ OCalculated: C: 50.30, H: 3.82, N: 16.75 Found: C: 50.56, H: 3.51, N:17.03

Example 110

Anti-HIV Activity

Anti-HIV activity for the compounds of the present invention was assayedby the method of Pauwel, et al, Pauwel, R., et al, J. VirologicalMethods (1988), 20, 309-321!.

Exponentially growing MT-4 cells were centrifuged, and the pellets wereresuspended in RPMI-1640 medium containing 10% fetal serum (serummedium). Portions of the cell suspension were either inoculated withHIV, or left uninfected. Serum medium was then further added to thesuspensions, which were then washed and centrifuged. The resultingpellets were then suspended in serum medium to a concentration of 4×10⁵cells/ml. Preparations of the test compound (in serum medium) weredeleted in a stepwise manner, and 100 μl of each of the solutions wereplaced in separated wells of a 96-well plastic microtitre plate. 100 μlof each of the cell suspensions (infected and non-infected) were thenadded to the wells, so that each dilution of each of the test compoundswas tested against both infected and non-infected cells. Blanks (notadded either of the cells) were also prepared. The preparations werethen cultured by standing the plate at 37° C. for 5 days in the presenceof 5 % carbon dioxide gas.

At the end of this time, living cells were assayed for CPE inhibitoryactivity by the spectrophotometric assay of the blue formazan producedby the reduction of MTT3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide! which wasadded to the preparations.

CPE inhibitory activity was defined as 100% in non-infected cells towhich no test compounds had been added, while CPE inhibitory activitywas defined as 0% in infected cells to which test compounds had not beenadded. The effective concentration (EC₅₀) of the compound at which 50%CPE inhibition was observed in HIV infected cells was then determined. Asecond index was then generated, concerning cellular cytotoxic activityof the compounds, by calculating the concentration (CC₅₀) at which thetest compounds caused 50% growth inhibition of non-infected cells.

Finally, a selective index (S.I.) was generated by calculating the valueof CC₅₀ /EC₅₀, to give an index of anti-HIV activity. The results areshown in Table 28.

Analysis of the preparations, at various stages, indicated that thecells and preparations consistently remained mycoplasma-free.

                  TABLE 28                                                        ______________________________________                                        Compound of Example                                                                             EC.sub.50 μg/ml                                                                      S.I.                                              ______________________________________                                         1                0.015     400                                                2                0.03      100                                                6                0.02      34                                                 7                0.22      113                                                8                0.1       500                                               17                0.5       250                                               18                0.07      121                                               19                0.07      57                                                21                0.037     16                                                23                0.021     309                                               24                0.07      257                                               29                0.05      22                                                37                0.23      >109                                              38                0.07      79                                                46                0.06      155                                               53                0.3       >83                                               63                0.01      1000                                              67                0.08      >500                                              (96)                                                                          70                0.5       20                                                85                1.0       17                                                87                0.074     >512                                              92                0.8       31                                                94                0.5       21                                                95                0.4       >62                                               99                1.0       >25                                               100               0.4       9                                                 ______________________________________                                    

As can be seen from the above Table, the compounds of the presentinvention are effective in very small doses, and also exhibit anextremely high selective index.

By contrast, the prior art compounds (shown in Tables 29 and 30 below),and which are known as antibacterials, all had an EC₅₀ in excess of 100μg/ml, when tested as above. Thus, the known compounds are at least 100times less effective than the compounds of the present invention asanti-HIV agents.

                  TABLE 29                                                        ______________________________________                                         ##STR60##                                                                    General name                                                                           Q         R.sup.1     R.sup.3                                                                              R.sup.4                                 ______________________________________                                        Enoxacin N         Ethyl       H      H                                       Ciprofloxacin                                                                          CH        Cyclopropyl H      H                                       Norfloxacin                                                                            CH        Ethyl       H      H                                       Ofloxacin                                                                              COCH.sub.2 CH(CH.sub.3)                                                                         Methyl   H                                         DR-3355  COCH.sub.2 CH(CH.sub.3)-(s)                                                                     Methyl   H                                         Lomefloxacin                                                                           CF        Ethyl       H      Methyl                                  Fleroxacin                                                                             CF        2-Fluoroethyl                                                                             Methyl H                                       Difloxacin                                                                             CH        4-Fluorophenyl                                                                            Methyl H                                       ______________________________________                                    

                  TABLE 30                                                        ______________________________________                                         ##STR61##                                                                    General name                                                                             R.sup.1      Q         R.sup.6                                                                           R.sup.8                                 ______________________________________                                        Tosufloxacin                                                                             2,4-Difluorophenyl                                                                         N         H   H                                       ______________________________________                                    

Reference example 1 Synthesis of6,7-difluoro-8-difluoromethoxy-1-(2-pyridylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR62##

In 37 ml of toluene was dissolved 30 g (0.124 mole) of2,4,5-trifluoro-3-difluoromethoxybenzoic acid, and 35 ml of thionylchloride and 0.5 ml of N,N-dimethylformamide were added thereto. Themixture was refluxed by heating for 4 hours. After the reaction, tolueneand excess thionyl chloride were removed under reduced pressure toobtain 2,4,5-trifluoro-3-difluoromethoxybenzoyl chloride.

Separately, 15.5 g (0.135 mole) of magnesium ethoxide and 20.9 g (0.130mole) of diethyl malonate were refluxed by heating in 100 ml ofanhydrous tetrahydrofuran for 2.5 hours under stirring to obtain atetrahydrofuran suspension of diethyl ethoxy magnesium malonate. To thesuspension was added dropwise a solution of the above acid chloridedissolved in 20 ml of tetrahydrofuran at room temperature understirring, and the mixture was further stirred at room temperature for 2hours. To the reaction mixture was added 100 ml of 1N hydrochloric acid,and the mixture was stirred vigorously. The mixture was separated, andthe organic layer was washed with water and dried over anhydrous sodiumsulfate. Then, the solvent was removed under reduced pressure to obtain51.8 g of diethyl 2,4,5-trifluoro-3-difluoromethoxybenzoylmalonate aspale red liquid.

MS spectrum (CI): m/e 385 (M⁺ +1) m/e 339 (M⁺ -OC₂ H₅)

Next, the liquid obtained was mixed with 200 ml of dioxane, and 23.6 g(0.124 mole) of p-toluenesulfonic acid.monohydrate was added thereto.The mixture was refluxed by heating for 8.5 hours. The reaction mixturewas concentrated under reduced pressure, to the residue were added waterand 10.41 g (0.124 mole) of sodium hydrogen carbonate, and the mixturewas extracted with ethyl acetate. The ethyl acetate layer was washedwith water, dried over anhydrous sodium sulfate and then concentratedunder reduced pressure to obtain 32.0 g of ethyl2,4,5-trifluoro-3-difluoromethoxybenzoylacetate as yellow liquid.

MS spectrum (CI): m/e 313 (M⁺ +1) m/e 225 (M⁺ -CH₂ COOC₂ H₅)

To 4.85 g (0.0155 mole) of ethyl2,4,5-trifluoro-3-difluoromethoxybenzoylacetate obtained as describedabove were added 11 ml of acetic anhydride and 3.2 ml of triethylorthoformate, and the mixture was refluxed by heating for 2 hours. Then,excess acetic anhydride and triethyl orthoformate were removed underreduced pressure. The residue was dissolved in 150 ml ofdichloromethane, and to the solution was added dropwise 2.01 g (0.0186mole) of 2-aminomethylpyridine under ice cooling and stirring. Themixture was stirred under ice cooling for 1 hour. The reaction mixturewas concentrated under reduced pressure, and the residue was applied tosilica gel column chromatography (the eluent used was a mixture oftoluene:ethyl acetate=9:1) to obtain 6.56 g of ethyl2-(2,4,5-trifluoro-3-difluoromethoxybenzoyl)-3-(2-pyridylmethylamino)acrylateas amber liquid. Recrystallization was carried out by using n-hexane toobtain 3.6 g of white crystals.

MS spectrum (CI): m/e 431 (M⁺ +1)

In 50 ml of N,N-dimethylformamide was dissolved 5.6 g (0.013 mole) ofethyl2-(2,4,5-trifluoro-3-difluoromethoxybenzoyl)-3-(2-pyridylmethylamino)acrylate,and 2.2 g (0.026 mole) of sodium hydrogen carbonate was added thereto.The mixture was stirred at 120° C. for 30 minutes. Then, the reactionmixture was poured into 200 ml of water, and crystals precipitated werecollected by filtration. The collected crystals were washed with waterand ethanol and dried to obtain 2.6 g of ethyl6,7-difluoro-8-difluoromethoxy-1-(2-pyridylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylateas yellow crystals.

MS spectrum (CI): m/e 411 (M⁺ +1)

Next, 1.7 g (0.0041 mole) of the ester compound was suspended in a mixedsolution of 4.2 ml of acetic acid, 1.5 ml of water and 0.48 ml of conc.sulfuric acid, and the suspension was refluxed by heating for 2 hoursunder stirring. After the suspension was cooled to room temperature,water was added thereto and insolubles were collected by filtration. Theinsolubles collected by filtration were washed with water and dried toobtain 1.1 g of6,7-difluoro-8-difluoromethoxy-1-(2-pyridylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid as white crystals.

Melting point: 207° to 213° C. (decomposed)

MS spectrum (CI): m/e 383 (M⁺ +1)

Reference examples 2 to 9

In the same manner as in Reference example 1, compounds shown in Table31 were synthesized.

                                      TABLE 31                                    __________________________________________________________________________     ##STR63##                                                                    Reference        Physical properties                                          example                                                                            R.sup.1     MS spectrum (CI)                                                                       m.p.     Shape                                      __________________________________________________________________________    2    H           m/e 292 (M.sup.+  + 1)                                                                 275 to 277° C.                                                                  White                                                       247 (M.sup.+CO.sub.2)                                                                           crystal                                    3    CH.sub.2 CH.sub.2 OH                                                                      m/e 336 (M.sup.+  + 1)                                                                 176 to 177° C.                                                                  White                                                       291 (M.sup.+CO.sub.2)                                                                           powder                                     4    CH.sub.2 CHCH.sub.2                                                                       m/e 332 (M.sup.+  + 1)                                                                 149 to 151° C.                                                                  White                                                       288 (M.sup.+CO.sub.2)                                                                           crystal                                    5    CH.sub.2 CCH                                                                              m/e 330 (M.sup.+  + 1)                                                                 168 to 169° C.                                                                  White                                                       285 (M.sup.+CO.sub.2)                                                                           crystal                                          ##STR64##  m/e 405 (M.sup.+  + 1)                                                                 161 to 167° C.                                                                  Slightly yellow powder                     7                                                                                   ##STR65##  m/e 363 (M.sup.+  + 1)                                                                 186 to 188° C.                                                                  White powder                               8    CH.sub.2 CH.sub.2 OCOCH.sub.3                                                             m/e 378 (M.sup.+  + 1)                                                                 115.5 to 116.6° C.                                                              White                                                       333 (M.sup.+CO.sub.2)                                                                           powder                                     9    CH.sub.2COOCH.sub.3                                                                       m/e 364 (M.sup.+  + 1)                                                                 187 to 189° C.                                                                  Slightly                                                                      yellow                                                                        powder                                     __________________________________________________________________________

Reference example 10 Synthesis of1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR66##

In 290 ml of acetic acid were dissolved 26.4 g (0.168 mole) of2-fluoro-6-nitrophenol and 17.2 g (0.168 mole) of acetic anhydride, and3.0 g of 5% palladium carbon was added thereto. Hydrogen gas was passedthrough the mixture, with stirring, at room temperature for 2 hours.After the reaction mixture had been filtered and the filtrateconcentrated under reduced pressure, the residue was extracted withethyl acetate. The ethyl acetate layer was washed with water and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was applied to silica gel columnchromatography (the eluent used was a mixture of ethylacetate:toluene=1:2) to obtain 25.9 g of 2-acetylamino-6-fluorophenol asbrown crystals.

MS spectrum (CI): m/e 170 (M⁺ +1) m/e 127 (M⁺ +1-COCH₃)

In 110 ml of N,N-dimethylformamide was dissolved 25.9 g (0.153 mole) of2-acetylamino-6-fluorophenol obtained as described above, and 25.4 g(0.184 mole) of potassium carbonate and 33.1 g (0.383 mole) ofchlorodifluoromethane were added thereto. The mixture was stirred in anautoclave at 100° C. for 5 hours. After completion of the reaction, thereaction mixture was poured into 1 l of water and extracted with ethylacetate. The ethyl acetate layer was washed with water and dried overanhydrous sodium sulfate. Then, the solvent was removed under reducedpressure, and the residue was applied to silica gel columnchromatography (the eluent used was a mixture of ethylacetate:toluene=1:3) to obtain 30.4 g of3-fluoro-2-difluoromethoxyacetanilide as slightly brownish crystals.

MS spectrum (CI): m/e 220 (M⁺ +1)

In 180 ml of ethyl alcohol was dissolved 30.3 g (0.138 mole) of3-fluoro-2-difluoromethoxyacetanilide obtained as described above, and50.3 ml of conc. hydrochloric acid was added thereto. The mixture wasrefluxed by heating for 3 hours. After completion of the reaction, ethylalcohol and conc. hydrochloric acid were removed under reduced pressure,and 200 ml of water was added to the residue. The mixture wasneutralized with potassium carbonate and then extracted with chloroform.The chloroform layer was washed with a saturated saline solution anddried over anhydrous sodium sulfate. Then, the solvent was removed underreduced pressure, and the residue was applied to silica gel columnchromatography (the eluent used was chloroform) to obtain 22.4 g of3-fluoro-2-difluoromethoxyaniline as red liquid.

A mixture of 22.4 g (0.127 mole) of 3-fluoro-2-difluoromethoxyanilineobtained as described above and 27.4 g (0.127 mole) of diethylethoxymethylenemalonate was heated at 120° C. for 5 hours. The mixturewas cooled to room temperature, n-hexane was added thereto, and themixture was filtered. Products collected by filtration was washed withn-hexane and dried to obtain 37.5 g ofN-(2,2-diethoxycarbonylvinyl)-3-fluoro-2-difluoromethoxyaniline as whitepowder.

A mixture of 10.0 g (0.029 mole) ofN-(2,2-diethoxycarbonylvinyl)-3-fluoro-2-difluoromethoxyaniline obtainedas described above and 70 ml of diphenyl ether was refluxed by heatingfor 30 minutes. The mixture was cooled to room temperature, and n-hexanewas added thereto. Crystals precipitated were collected by filtrationand dried to obtain 5.25 g of ethyl7-fluoro-8-difluoromethoxy-4-hydroxyquinoline-3-carboxylate as whitepowder.

Melting point: 218° to 219° C.

MS spectrum (CI). m/e 302 (M⁺ +1)

In 96 ml of N,N-dimethylformamide was dissolved 3.0 g (0.01 mole) ofethyl 7-fluoro-8-difluoromethoxy-4-hydroxyquinoline-3-carboxylateobtained as described above, and 6.9 g (0.05 mole) of potassiumcarbonate and 12.5 g (0.08 mole) of ethyl iodide were added thereto. Themixture was stirred at 100° C. for 14 hours. After completion of thereaction, the solvent was removed under reduced pressure, and water wasadded to the residue. Crystals precipitated were collected by filtrationand applied to silica gel column chromatography (the eluent used was amixture of chloroform:methanol=95:5) to obtain 1.1 g of ethyl1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylateas white crystals.

Melting point: 214.5° to 215.5° C.

MS spectrum (CI): m/e 329 (M⁺ +1)

Next, 1.1 g (0.0033 mole) of the ester compound was suspended in a mixedsolution of 9 ml of acetic acid, 6.6 ml of water and 1.2 ml of conc.sulfuric acid, and the suspension was refluxed by heating for 2 hoursunder stirring. After the suspension was cooled to room temperature,water was added thereto and insolubles were collected by filtration. Theinsolubles collected by filtration were washed with water and dried toobtain 0.85 g of1-ethyl-7-fluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid as white crystals.

Melting point: 169° to 170° C.

MS spectrum (CI): m/e 302 (M⁺ +1)

Reference example 11 Synthesis of3-cyano-1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline##STR67##

To 36.0 g (0.15 mole) of 2,4,5-trifluoro-3-difluoromethoxybenzoic acidwere added 45 ml of toluene, 15 ml of thionyl chloride and 0.2 ml ofN,N-dimethylformamide, and the mixture was refluxed by heating for 4hours. After the reaction, toluene and excess thionyl chloride wereremoved under reduced pressure to obtain2,4,5-trifluoro-3-difluoromethoxybenzoyl chloride.

In 75 ml of anhydrous tetrahydrofuran was dissolved 15.2 g (0.158 mole)of 3-dimethylaminoacrylonitrile, and 16.7 g (0.165 mole) oftriethylamine was added thereto. To the mixture was gradually addeddropwise at room temperature a solution of the above acid chloridedissolved in 15 ml of anhydrous tetrahydrofuran. After completion of thedropwise addition, the mixture was refluxed by heating for one hour,cooled to room temperature and then filtered. To the filtrate were added9.7 ml of triethylamine and 14.7 g (0.18 mole) of ethylaminehydrochloride, and the mixture was stirred at 40° C. for 2 hours. Themixture was cooled to room temperature and then filtered. The filtratewas concentrated under reduced pressure, and the residue was applied tosilica gel column chromatography (the eluent used was a mixture of ethylacetate:toluene=3:7) to obtain 39.3 g of2-(2,4,5-trifluoro-3-difluoromethoxybenzoyl)-3-ethylaminoacrylonitrileas red liquid. The product was dissolved in 700 ml of a mixed solutionof anhydrous diethyl ether and tetrahydrofuran, and 4.9 g (0.123 mole)of a 60% sodium hydride-mineral oil was gradually added thereto underice cooling. The mixture was stirred at the same temperature for onehour. By adding 120 ml of a 1N hydrochloric acid to the reaction mixtureand stirring the mixture vigorously, the whole reaction mixture was madeacidic. Crystals precipitated were collected by filtration, washed withwater and then washed with diethyl ether to obtain 17.2 g of3-cyano-1-ethyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinolineas white powder.

Melting point: 194° to 195° C.

MS spectrum (CI): m/e 301 (M⁺ +1)

Reference example 12 Synthesis of1-(4,6-dimethoxy-2-pyrimidinyl)piperazine ##STR68##

In 100 ml of acetonitrile was dissolved 10 g (0.0567 mole) of1-benzylpiperazine, and 11.7 g (0.085 mole) of potassium carbonate and14.8 g (0.068 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine wereadded thereto. The mixture was refluxed by heating for 5 hours. Themixture was cooled to room temperature and then filtered. The filtratewas concentrated under reduced pressure, and the residue was applied tosilica gel column chromatography (the eluent used was a mixture of ethylacetate:toluene=1:9) to obtain 17.6 g of4-(4,6-dimethoxy-2-pyrimidinyl)-1-benzylpiperazine as colorless liquid.

MS spectrum (CI): m/e 315 (M⁺ +1)

In 110 ml of ethanol was dissolved 3.9 g (0.0125 mole) of4-(4,6-dimethoxy-2-pyrimidinyl)-1-benzylpiperazine obtained as describedabove, and 2.5 g of 5% palladium carbon was added thereto. Whilerefluxing the mixture under heating, hydrogen gas was passed for 6hours. The reaction mixture was cooled to room temperature and thenfiltered. The filtrate was concentrated under reduced pressure, and theresidue was applied to silica gel column chromatography (the eluent usedwas a mixture of chloroform:methanol=9:1) to obtain 1.38 g of1-(4,6-dimethoxy-2-pyrimidinyl)piperazine as pale red crystals.

MS spectrum (CI): m/e 225 (M⁺ +1)

Reference example 13 Synthesis of 1-(6-methoxy-2-pyridyl)piperazine##STR69##

In a sealed tube, 8.6 g of piperazine and 2.9 g (0.02 mole) of2-chloro-6-methoxypyridine were reacted at 150° C. for 4 hours. Afterthe reaction, the reaction mixture was applied to silica gel columnchromatography (the eluent used was a mixture of chloroform:methanol:28% aqueous ammonia=40:9:1) to obtain 2.4 g of1-(6-methoxy-2-pyridyl)piperazine as pale yellow liquid.

MS spectrum (CI): m/e 194 (M⁺ +1)

Reference example 14 Synthesis of 1-(2-thiazolyl)piperazine ##STR70##

In 50 ml of acetonitrile was dissolved 5.0 g (0.0305 mole) of2-bromothiazole, and 13.3 g (0.153 mole) of piperazine, 8.4 g (0.061mole) of potassium carbonate and a catalytic amount of potassium iodidewere added thereto. The mixture was refluxed by heating for 5 hours. Themixture was cooled to room temperature and then filtered. The filtratewas concentrated under reduced pressure, and the residue was applied tosilica gel column chromatography (the eluent used was a mixture ofchloroform:methanol: 28% aqueous ammonia=40:9:1) to obtain 3.62 g of1-(2-thiazolyl)piperazine as colorless liquid.

MS spectrum (CI): m/e 170 (M⁺ +1)

Reference example 15 Synthesis of 1-(3-amino-2-pyridyl)piperazine##STR71##

In 30 ml of methanol was dissolved 3.13 g (0.015 mole) of1-(3-nitro-2-pyridyl)piperazine, and 2 g of 5% palladium carbon wasadded thereto. While stirring the mixture at room temperature, hydrogengas was passed through for one hour. The reaction mixture was filtered,and the filtrate was concentrated under reduced pressure to obtain 2.56g of 1-(3-amino-2-pyridyl)piperazine as pale yellow liquid.

MS spectrum (CI): m/e 179 (M⁺ +1)

Reference example 16 Synthesis of 1-(2-benzoxazolyl)piperazine ##STR72##

In 200 ml of acetonitrile were dissolved 33.6 g (0.39 mole) ofpiperazine and 10.0 g (0.065 mole) of 2-chlorobenzoxazole, and 9.0 g(0.065 mole) of potassium carbonate and a catalytic amount of potassiumiodide were added thereto. The mixture was refluxed by heating for 11hours under stirring. The mixture was cooled to room temperature andthen filtered. The filtrate was concentrated under reduced pressure, andthe residue was applied to silica gel column chromatography (the eluentused was a mixture of chloroform:methanol=9:1) to obtain 7.54 g of1-(2-benzoxazolyl)piperazine as white crystals.

MS spectrum (CI): m/e 204 (M⁺ +1)

Reference example 17 Synthesis of 3-hydroxy-4-phenylaminopyrrolidinehydrochloride ##STR73##

(1) In 20 ml of ethyl alcohol was dissolved 5 g (0.027 mole) of1-t-butoxycarbonyl-3-epoxypyrrolidine, and 12.6 g (0.135 mole) ofaniline was added thereto. The mixture was refluxed by heating for 20hours. After the mixture was cooled to room temperature, the solvent wasremoved under reduced pressure, and the residue was applied to silicagel column chromatography (the eluent used was a mixture of ethylacetate:toluene=1:4) to obtain 4.85 g of1-t-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine as yellowish browncrystals.

MS spectrum (EI): m/e 278 (M⁺) m/e 57 (C₄ H₉ ⁺)

(2) In 100 ml of methanol was dissolved 2.4 g (0.0086 mole) of1-t-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine obtained asdescribed above, and 30 ml of 6N hydrochloric acid was added thereto.After the mixture was refluxed by heating for 2.5 hours, the solvent wasremoved under reduced pressure. The resulting residue was washed withethanol and ether to obtain 1.52 g of 3-hydroxy-4-phenylaminopyrrolidinehydrochloride as light brown powder.

MS spectrum (CI): m/e 179 (M⁺ +1)

Reference example 18 Synthesis of 3-methoxy-4-phenylaminopyrolidinehydrochloride ##STR74##

To 10 ml of anhydrous tetrahydrofuran was added 0.34 g (0.0085 mole) ofa 60% sodium hydride-mineral oil, and while stirring the mixture at 45°to 50° C., 1.21 g (0.0085 mole) of methyl iodide was added thereto. Tothe mixture was added dropwise a solution of 2.37 g of1-t-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine obtained inReference example 17 (1) dissolved in 10 ml of anhydroustetrahydrofuran, and the mixture was further stirred at the sametemperature for 1 hour. After the mixture was cooled to roomtemperature, the solvent was removed under reduced pressure, and theresidue was spplied to silica gel column chromatography (the eluent usedwas a mixture of methyl acetate:toluene=1:4) to obtain 1.98 g of1-t-butoxycarbonyl-3-methoxy-4-phenylaminopyrrolidine as white crystals.

MS spectrum (CI): m/e 292 (M⁺)

In 100 ml of methanol was dissolved 1.98 g (0.0068 mole) of1-t-butoxycarbonyl-3-methoxy-4-phenylaminopyrrolidine obtained asdescribed above, and 23.5 ml of 6N hydrochloric acid was added thereto.The mixture was left to stand at room temperature overnight. The solventwas removed under reduced pressure, and the residue was washed withethanol to obtain 1.71 g of 3-methoxy-4-phenylaminopyrrolidinehydrochloride as white powder.

MS spectrum (CI): m/e 193 (M⁺ +1)

Reference example 19 Synthesis of 1-(6-ethyl-4-pyrimidinyl)piperazine##STR75##

To 12.4 g (0.1 mole) of 6-ethyl-4-hydroxypyrimidine was added 50 ml of1,2-dichloroethane, and 18.4 g (0.12 mole) of phosphorus oxychloride wasadded thereto. The mixture was refluxed by heating for 3 hours. Aftercooling, water was added to the reaction mixture, and the mixture wasextracted with chloroform. The chloroform layer was washed with waterand dried over anhydrous sodium sulfate. The solvent was removed underreduced pressure to obtain 10.38 g of 4-chloro-6-ethylpyrimidine asslightly red liquid.

Next, the liquid was mixed with 100 ml of acetonitrile, and to thesolution were added 11.5 g (0.073 mole) of 1-ethoxycarbonylpiperazine,20.2 g (0.146 mole) of potassium carbonate and a catalytic amount ofpotassium iodide. The mixture was refluxed by heating for 10 hours. Thereaction mixture was cooled to room temperature and then filtered.

The filtrate was concentrated under reduced pressure, and the residuewas applied to silica gel column chromatography (the eluent used was amixture of chloroform:methanol=4:1) to obtained 20.69 g of1-(6-ethyl-4-pyrimidinyl)-4-ethoxycarbonylpiperazine as orange liquid.

MS spectrum (CI): m/e 265 (M⁺ +1)

To 20.69 g (0.78 mole) of1-(6-ethyl-4-pyrimidinyl)-4-ethoxycarbonylpiperazine obtained asdescribed above was added 200 ml of 6N hydrochloric acid, and themixture was refluxed by heating for 18 hours. The reaction mixture wasadjusted to pH 10 or more by adding sodium hydroxide, and extracted withdiethyl ether. The organic layer was dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas applied to silica gel column chromatography (the eluent used was amixture of chloroform:methanol=4:1) to obtain1-(6-ethyl-4-pyrimidinyl)piperazine as colorless liquid.

MS spectrum (CI): m/e 193 (M⁺ +1)

Reference example 20 Synthesis of9-ethyl-6,7-difluoro-8-difluoromethoxy-2,3,4,9-tetrahydroisothiazolo5,4-b!quinolin-3,4-dione ##STR76##

According to the method as described in Reference example 23 of JapaneseProvisional Patent Publication No. 209367/1991, the reaction was carriedout to obtain the title compound as a pale pink powder.

Melting point: 211° to 213° C.

MS spectrum (CI): m/e 349 (M⁺ +1)

We claim:
 1. A compound of formula (Ia) or a pharmaceutically acceptablesalt or ester thereof: ##STR77## in which X represents a fluorine atom;Yrepresents a hydrogen atom, a halogen atom, a lower alkyl group, anunsubstituted amino group, or an amino group substituted by one or twogroups selected from the group consisting of a lower alkyl group and anaralkyl group; Z represents a protected or an unprotected carboxyl groupor a 5-tetrazolyl group; Q represents a group of formula (d): ##STR78##R¹ and R² together represent a group of formula (f): ##STR79## wherein Arepresents a hydrogen atom, or a lower alkyl group which isunsubstituted or substituted by at least one substituent selected fromthe group consisting of a halogen atom, a hydroxy group and a loweralkoxy group; G represents a nitrogen atom or a group of formula (g):##STR80## G² represents a methylene group, a carbonyl group, an oxygenatom or a group of formula --N(R¹¹)--, where R¹¹ represents a hydrogenatom or a lower alkyl group; p=1 or 1; R represents a group of formula(h) or (i): ##STR81## wherein R³ is a 5- or 6-membered aromaticheteromonocyclic group having one or two heteroatoms selected from thegroup consisting of N, O and S, which is unsubstituted or substituted byat least one substituent R.sup. as defined below, or a fused aromaticgroup which is a benzene ring fused with a 5- or 6-membered aromaticheteromonocyclic group having one or two heteroatoms selected from thegroup consisting of N, O and S, which is unsubstituted or substituted byat least one substituent R⁰ as defined below; R⁶ is an aryl group whichis unsubstituted or substituted by at least one substituent R⁰ asdefined below, a 5- or 6-membered aromatic heterocyclic group having oneor two heteroatoms selected from the group consisting of N, O and S,which is unsubstituted or substituted by at least one substituent R⁰ asdefined below, or a fused aromatic group which is a benzene ring fusedwith a 5- or 6-membered aromatic heteromonocyclic group having one ortwo heteroatoms selected from the group consisting of of N, O and S,which is unsubstituted or substituted by at least one substituent R⁰ asdefined below; R⁴, R⁵ and R⁷ are the same or different, and eachrepresents a hydrogen atom or a lower alkyl group; R⁸ represents ahydrogen atom, a lower alkyl group, a hydroxy group or a lower alkoxygroup; n=1 or 2; m=0 or 1; n'=1 or 2; and n"=1, 2, 3 or 4;andsubstituent R⁰ is selected from the group consisting of halogen atoms,nitro groups, hydroxy groups, lower alkyl groups which are unsubstitutedor substituted with at least one halogen atom, lower alkoxy group, andamino groups which are unsubstituted or substituted with one or twolower alkyl groups, and when there are two or more substituents R⁰, eachare the same or different.
 2. The compound according to claim 1, whereinR¹ and R² are linked together to be a group of formula --O--CH₂ --CH(A')wherein A' represents a hydrogen atom or a lower alkyl which isunsubstituted or substituted by at least one halogen atom.
 3. Thecompound according to claim 2, wherein A' represents a monofluoromethylgroup.
 4. The compound according to claim 1, wherein said R representsthe group of formula (h) and R³ represents either a 5- or 6-memberedaromatic heteromonocyclic group containing one or two nitrogen atomswhich is unsubstituted or substituted by R⁰, or a fused group of said 5-or 6-membered aromatic heteromonocyclic group fused with a benzene ringwhich is unsubstituted or substituted by R⁰.
 5. The compound accordingto claim 1, wherein said R represents the group of formula (h) and R³represents an aromatic heteromonocyclic group which is unsubstituted orsubstituted by R⁰.
 6. The compound according to claim 1, wherein said Rrepresents a group of formula (i) and R⁶ represents either a 5- or6-membered aromatic heteromonocyclic group containing one or twonitrogen atoms which is unsubstituted or substituted by R⁰, or a fusedgroup of said 5- or 6-membered aromatic heteromonocyclic group fusedwith a benzene ring which is unsubstituted or substituted by R⁰.
 7. Thecompound according to claim 1, wherein said R represents the group offormula (h).
 8. The compound according to claim 1, wherein said Rrepresents the group of formula (h) and R³ represents a 5- or 6-memberedaromatic heteromonocyclic group having one or two nitrogen atoms.
 9. Thecompound according to claim 5, wherein R³ is a pyridyl group, apyrazinyl group or a pyrimidinyl group, and is unsubstituted orsubstituted by at least one substituent R⁰.
 10. The compound accordingto claim 9, wherein said R is 4-(2-pyrimidinyl)-piperazin-1-yl group.11. Compounds according to claim 1, wherein Z is a carboxyl group. 12.An anti-HIV composition comprising an effective anti-HIV amount of acompound according to claim 1 as an effective ingredient, together witha pharmaceutically acceptable carrier therefor.
 13. A method of treatinga patient suffering with AIDS comprising administering to the patient apharmaceutically effective anti-HIV amount of the compound according toclaim 1, or a pharmaceutically acceptable salt or ester thereof, eitheralone, or in admixture with a pharmaceutically acceptable carrier. 14.The compound according to claim 1, wherein said Z represents anunprotected carboxyl group or a carboxyl group protected by anunsubstituted C₁ to C₄ alkyl, aralkyl, C₁ to C₄ alkanoyloxyalkyl, C₁ toC₄ alkoxycarbonyloxyalkyl, N,N-dialkyl-substituted aminocarbonylalkyl,N,N-dialkyl-substituted aminoalkyl, alkyl substituted by a 5- or6-membered saturated monocyclic group having one or two hetero atomsselected from the group consisting of N, O and S,5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl group or5-phenyl-2-oxo-1,3-dioxolen-4-yl-methyl group.
 15. The compoundaccording to claim 1, wherein the compound is9-fluoro-3-fluoromethyl-10-4-(2-pyrimidinyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid.
 16. The compound according to claim1, wherein the compound is 9-fluoro-3-fluoromethyl-10-4-(2-pyridyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid.
 17. The compound according to claim1, wherein the compound is 9-fluoro-3-methyl-10-4-(2-pyridyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid.
 18. The compound according to claim1, wherein the compound is 9-fluoro-10-4-(2-pyrimidinyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido1,2,3-de!1,4!benzoxazine-6-carboxylic acid.
 19. The composition according toclaim 12, wherein the compound is at least one compound selected fromthe group consisting of:9-fluoro-3-fluoromethyl-10-4-2(-pyrimidinyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid, 9-fluoro-3-fluoromethyl-10-4-(2-pyridyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid, 9-fluoro-3-methyl-10-4-(2-pyridyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid, and 9-fluoro-10-4-(2-pyrimidinyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine -6-carboxylic acid.
 20. The method according to claim13, wherein the compound is at least one compound selected from thegroup consisting of:9-fluoro-3-fluoromethyl-10-4-(2-pyrimidinyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid, 9- fluoro-3-fluoromethyl -10-4-(2-pyridyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid, 9-fluoro-3-methyl-10-4-(2-pyridyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid, and 9-fluoro-10-4-(2-pyrimidinyl)piperazin-1-yl!-2,3-dihydro-7-oxo-7H-pyrido 1,2,3-de!1,4!benzoxazine-6-carboxylic acid.
 21. A method of inhibiting HIVreplication or inhibiting the cytopathic effect of HIV in a patientcomprising administering to a patient in need thereof an effectiveanti-HIV amount of the compound according to claim 1 or apharmaceutically acceptable salt or ester thereof, either alone, or inadmixture with a pharmaceutically acceptable carrier.